Method and drug for preventing and treating blood pressure abnormalities

Abstract

To provide pharmaceutical compositions for treating blood pressure abnormalities and complications thereof.SOLUTION: Provided is a drug for preventing or treating hypertension, comprising one or more compounds selected from components of a plasminogen activation pathway, compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway, compounds for mimicking the activity of plasminogen or plasmin, compounds capable of upregulating the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to methods and medicaments for treating dystensive disorders and their complications. [Background technology]

[0002] Hypertension is one of the most prevalent diseases in the world, and its incidence in China is increasing year by year. Hypertension can cause complications in internal organs such as the heart, brain, and kidneys, leading to disability and death. The harm of hypertension is that it can lead to lesions in multiple organs and systems such as the heart, brain, and kidneys, with the most common complication being stroke. And hypertension leads to associated cardiac damage, such as myocardial hypertrophy, coronary artery sclerosis, arrhythmia, and heart failure. Hypertension is also often accompanied by kidney damage and peripheral vascular disease. When hypertension progresses to the mid- to late-stage stage, retinopathy may occur. Diabetes is also one of the common complications of hypertension. Research on the prevention and treatment of hypertension has attracted the attention of scholars around the world. And by effectively preventing and treating the complications of hypertension, the morbidity and mortality of patients can be significantly reduced.

[0003] The present invention discovers that plasminogen can significantly reduce hypertension while improving tissue and organ damage, fibrosis and dysfunction caused by hypertension, opening up new avenues for the prevention and treatment of hypertension and related diseases and complications. Summary of the Invention

[0004] This application relates to methods, uses and medicaments of components of the plasminogen activation pathway, such as plasminogen, in the prevention and treatment of abnormal blood pressure (including hypertension and hypotension). Research has demonstrated that components of the plasminogen activation pathway, such as plasminogen, can promote the return of blood pressure to normal in subjects suffering from hypertension or hypotension, as well as reduce and alleviate the structural and functional damage to tissues and organs, such as the heart, lungs, kidneys and liver, caused by abnormal blood pressure (e.g., hypertension or hypotension).

[0005] Specifically, the present invention relates to the following:

[0006] In one aspect, the present application relates to a method of preventing or treating hypertension comprising administering to a hypertensive subject an effective amount of one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.

[0007] In one aspect, the present application also relates to the use of one or more compounds selected from components of the plasminogen activation pathway, compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds capable of upregulating the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs and antagonists of fibrinolysis inhibitors in the preparation of a medicament for preventing or treating hypertension.

[0008] In one aspect, the present application also relates to an agent for preventing or treating hypertension comprising one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.

[0009] In one aspect, the present application also relates to the use of one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs and antagonists of fibrinolysis inhibitors in the prevention or treatment of hypertension.

[0010] 2. The method, use or agent according to item 1, wherein the component of the plasminogen activation pathway is selected from plasminogen, recombinant human plasminogen, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogues containing one or more kringle domains and protease domains of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activators, tPA and uPA.

[0011] 3. The method, use or medicament according to item 1, wherein the fibrinolysis inhibitor antagonist is an inhibitor of PAI-1, complement C1 inhibitor, alpha2-antiplasmin or alpha2-macroglobulin, such as an antibody.

[0012] 4. The method, use, or medication according to item 1, wherein the hypertension includes damage or complications to the heart, brain, lungs, liver, kidneys, or blood vessels due to high blood pressure.

[0013] Item 5. The method, use, or medicament according to item 4, wherein the complications include arrhythmia, heart failure, cerebral hemorrhage, cerebral thrombosis, cerebral infarction, hypertensive nephropathy, renal failure, uremia, liver cirrhosis, pulmonary hypertension, pulmonary fibrosis, and microthrombosis.

[0014] 6. The method, use, or medicament according to any one of items 1 to 5, wherein the compound has one or more effects selected from the effect of lowering blood pressure in a hypertensive subject, the effect of lowering serum angiotensin II level in a hypertensive subject, the effect of regulating the level of ACE or ACE2 in a subject, the effect of reducing damage to tissues and organs caused by hypertension, the effect of promoting the repair of damaged tissues and organs, the effect of reducing fibrosis in tissues and organs, and the effect of promoting the elimination of free radicals.

[0015] 7. The method, use, or medicament according to item 6, wherein promoting the repair of damaged tissues and organs is promoting the recovery of structure or function of damaged cardiac tissue, brain tissue, lung tissue, kidney tissue, or liver tissue.

[0016] 8. The method, use, or medicament according to item 6, wherein reducing fibrosis in the tissues and organs comprises reducing fibrosis in cardiac tissue, lung tissue, kidney tissue, or liver tissue.

[0017] Item 9. The method, use or agent according to item 6, wherein the compound scavenges free radicals by promoting SOD production.

[0018] 10. The method, use, or agent according to any one of items 1 to 9, wherein the compound is plasminogen.

[0019] 11. The method, use, or agent according to any one of items 1 to 9, wherein the plasminogen has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2 and has plasminogen proteolytic activity or lysine-binding activity.

[0020] 12. The method, use or agent according to any one of items 1 to 11, wherein the plasminogen comprises a plasminogen active fragment as shown in sequence 14 and has plasminogen proteolytic activity.

[0021] 13. The method, use, or agent according to any one of items 1 to 9, wherein the plasminogen is selected from Glu-plasminogen, Lys-plasminogen, miniplasminogen, microplasminogen, delta-plasminogen, or mutants thereof that retain plasminogen proteolytic activity.

[0022] 14. The method, use or agent according to any one of items 1 to 9, wherein the plasminogen is natural or synthetic human plasminogen, or a variant or fragment thereof that retains the proteolytic activity or lysine-binding activity of plasminogen.

[0023] 15. The method, use or agent according to any one of items 1 to 14, wherein the compound is used in combination with one or more other therapeutic methods or agents.

[0024] 16. The method, use or medicament according to item 15, wherein the other medicament comprises an antihypertensive drug, a hormone, an immunosuppressant, an antibiotic or an antiviral drug.

[0025] 17. The method, use or medicament according to any one of clauses 1 to 16, wherein the compound is administered by nasal inhalation, aerosol inhalation, nasal drops, ear drops or eye drops, administered intravenously, intraperitoneally, subcutaneously, intracranially, intrathecally, intraarterially, intrarectally and / or intramuscularly.

[0026] The present invention also relates to the following:

[0027] In one aspect, the present application relates to a method of preventing or treating abnormal blood pressure or blood pressure disorders comprising administering to a subject suffering from abnormal blood pressure an effective amount of one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.

[0028] In one aspect, the present application also relates to the use of one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs and antagonists of fibrinolysis inhibitors, in the preparation of a medicament for preventing or treating abnormal blood pressure or blood pressure dysregulations.

[0029] In one aspect, the present application also relates to an agent for preventing or treating abnormal blood pressure or blood pressure dysregulations, comprising one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.

[0030] In one aspect, the present application also relates to the use of one or more compounds selected from components of the plasminogen activation pathway, compounds that can activate plasminogen directly or indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds that can upregulate the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors, in the prevention or treatment of abnormal blood pressure or blood pressure dysregulations.

[0031] Said abnormal blood pressure or blood pressure abnormality of the present application includes hypertension or hypertension, where blood pressure is higher than normal level, and hypotension or hypotension, where blood pressure is lower than normal level.Accordingly, the present application relates to methods, uses and medicaments for restoring hypertension in a hypertensive subject or hypotension in a hypotensive subject to normal level using one or more of the above compounds.

[0032] 2. The method, use or agent according to item 1, wherein the component of the plasminogen activation pathway is selected from plasminogen, recombinant human plasminogen, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogues containing one or more kringle domains and protease domains of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activators, tPA and uPA.

[0033] 3. The method, use or medicament according to item 1, wherein the fibrinolysis inhibitor antagonist is an antagonist of PAI-1, complement C1 inhibitor, alpha2-antiplasmin or alpha2-macroglobulin, e.g. an antibody.

[0034] 4. The method, use, or medicament according to any one of items 1 to 3, wherein the blood pressure abnormality includes tissue and organ damage or complications caused by blood pressure abnormality. In some embodiments, the tissue and organ damage or complications are damage or complications of the heart, brain, lung, liver, kidney, or blood vessels. In some embodiments, the tissue and organ damage is structural damage to tissues and organs (e.g., changes in the structure of normal tissues) or functional damage to tissues and organs (e.g., impaired function of tissues and organs).

[0035] In the above embodiment, the blood pressure abnormality comprises hypertension or hypotension.

[0036] Item 5. The method, use, or medication according to item 4, wherein the complication caused by abnormal blood pressure is a complication caused by hypertension, and includes arrhythmia, heart failure, coronary heart disease, cerebral hemorrhage, cerebral thrombosis, cerebral infarction, hypertensive nephropathy, renal failure, uremia, liver cirrhosis, pulmonary hypertension, pulmonary fibrosis, or microthrombosis.

[0037] Item 5. The method, use, or medicament according to Item 4, wherein the complication caused by abnormal blood pressure is a complication caused by hypotension, including insufficient blood supply to tissues and organs due to hypotension, such as insufficient blood supply to the heart, angina pectoris, shock, insufficient blood supply to the brain, syncope, cerebral infarction, insufficient blood supply to the kidney, oliguria, proteinuria, and renal insufficiency.

[0038] 6. The method, use, or medicament according to any one of items 1 to 5, wherein the compound has one or more effects selected from the effect of lowering blood pressure in a hypertensive subject, the effect of lowering serum angiotensin II level in a hypertensive subject, the effect of regulating ACE or ACE2 level in a subject, the effect of increasing blood pressure in a hypotensive subject, the effect of promoting the return of blood pressure in a hypertensive or hypotensive subject to a normal level, the effect of reducing damage to tissues and organs caused by hypertension or hypotension, the effect of promoting the repair of damaged tissues and organs, the effect of reducing fibrosis in tissues and organs, and the effect of promoting the elimination of free radicals.

[0039] 7. The method, use, or agent according to any one of items 1 to 6, wherein promoting repair of damaged tissues and organs is promoting recovery of structure or function of damaged cardiac tissue, brain tissue, lung tissue, kidney tissue, or liver tissue.

[0040] 8. The method, use, or medicament according to any one of items 1 to 7, wherein reducing fibrosis of the tissues and organs includes reducing fibrosis of cardiac tissue, lung tissue, kidney tissue, or liver tissue.

[0041] 9. The method, use, or agent according to any one of items 1 to 8, wherein the compound scavenges free radicals by promoting SOD production.

[0042] 10. The method, use, or agent according to any one of items 1 to 9, wherein the compound is plasminogen.

[0043] 11. The method, use, or agent according to any one of items 1 to 10, wherein the plasminogen has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2 and has plasminogen proteolytic activity or lysine-binding activity.

[0044] 12. The method, use or agent according to any one of items 1 to 11, wherein the plasminogen comprises a plasminogen active fragment as shown in sequence 14 and has plasminogen proteolytic activity.

[0045] 13. The method, use, or agent according to any one of items 1 to 12, wherein the plasminogen is selected from Glu-plasminogen, Lys-plasminogen, miniplasminogen, microplasminogen, delta-plasminogen, or mutants thereof that retain plasminogen proteolytic activity.

[0046] 14. The method, use or agent according to any one of items 1 to 13, wherein the plasminogen is natural or synthetic human plasminogen, or a variant or fragment thereof that retains the proteolytic activity or lysine-binding activity of plasminogen.

[0047] 15. The method, use or agent according to any one of items 1 to 14, wherein the compound is used in combination with one or more other therapeutic methods or agents.

[0048] Item 16. The method, use, or medicament according to item 15, wherein the other medicament is a medicament for treating a disease other than abnormal blood pressure in a subject with abnormal blood pressure.

[0049] 17. The method, use or medicament according to any one of clauses 1 to 16, wherein the compound is administered by nasal inhalation, aerosol inhalation, nasal drops, ear drops or eye drops, administered intravenously, intraperitoneally, subcutaneously, intracranially, intrathecally, intraarterially, intrarectally and / or intramuscularly.

[0050] One aspect of the invention also relates to plasminogen, plasminogen-containing agents, pharmaceutical compositions, kits, and articles of manufacture for preventing or treating blood pressure abnormalities (e.g., hypertension or hypotension) and associated damage or complications in a subject.

[0051] One aspect of the present invention also relates to plasminogen- or plasminogen-containing drugs, pharmaceutical compositions, kits, and products, and to the use of the plasminogen- or plasminogen-containing drugs, pharmaceutical compositions, kits, and products of the above methods in preventing or treating blood pressure abnormalities (e.g., hypertension or hypotension) and associated damage or complications in a subject.

[0052] In any one of the above embodiments of the present application, the plasminogen may have at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2, 6, 8, 10 or 12 and still have plasminogen activity. In some embodiments, the plasminogen is a protein in which 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1 amino acids are added, deleted and / or substituted based on sequence 2, 6, 8, 10 or 12 and still have proteolytic activity or lysine binding activity.

[0053] In some embodiments, the plasminogen is a protein that includes a proteolytic or lysine-binding active fragment and still has proteolytic or lysine-binding activity. In some embodiments, the plasminogen is Glu-plasminogen, Lys-plasminogen, miniplasminogen, microplasminogen, δ-plasminogen, or a variant thereof that retains proteolytic or lysine-binding activity. In the above embodiments, the plasminogen is natural or synthetic human plasminogen, or a variant or fragment thereof that still retains plasminogen activity. In some embodiments, the plasminogen is an orthologue of human plasminogen from a primate or rodent, or a variant or fragment thereof that still retains proteolytic or lysine-binding activity. In some embodiments, the amino acid sequence of the plasminogen is set forth in sequence 2, 6, 8, 10, or 12. In some embodiments, the plasminogen is human natural plasminogen.

[0054] In some embodiments, the subject is a human. In some embodiments, the subject is deficient or lacking in plasminogen. In some embodiments, the deficient or lacking is congenital, inherited and / or localized.

[0055] In some embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable carrier and plasminogen for use in the aforementioned methods. In some embodiments, the kit may be a prophylactic or therapeutic kit comprising (i) plasminogen for use in the aforementioned methods, and (ii) means for delivering the plasminogen to the subject. In some embodiments, the means is a syringe or a vial. In some embodiments, the kit further comprises a label or a protocol for instructing administration of the plasminogen to the subject to perform any of the aforementioned methods.

[0056] In some embodiments, the article of manufacture comprises a container containing a label and (i) plasminogen or a pharmaceutical composition containing plasminogen for use in the aforementioned methods, the label providing instructions for administering the plasminogen or composition to the subject to perform any of the aforementioned methods.

[0057] In some embodiments, the kit or article of manufacture further comprises one or more additional components or containers that contain other agents.

[0058] In some embodiments of the method, the plasminogen is administered systemically or locally, preferably by nasal inhalation, aerosol inhalation, nasal drops, ear drops, or eye drops, and the treatment is by administering plasminogen intravenously, intraperitoneally, subcutaneously, intracranially, intrathecally, intraarterially, intrarectally, and / or intramuscularly. In some embodiments of the method, the plasminogen is administered in combination with a suitable polypeptide carrier or stabilizer. In some embodiments of the method, the plasminogen is administered daily at a dose of 0.0001-2000 mg / kg, 0.001-800 mg / kg, 0.01-600 mg / kg, 0.1-400 mg / kg, 1-200 mg / kg, 1-100 mg / kg, 10-100 mg / kg (calculated per kilogram of body weight), or 0.0001-2000 mg / cm 2 , 0.001-800mg / cm 2 , 0.01-600mg / cm 2 , 0.1-400mg / cm 2 , 1-200mg / cm 2 , 1-100mg / cm 2 , 10-100mg / cm 2 (calculated per square centimeter of body surface area) and is preferably administered one or more times, preferably at least daily.

[0059] The present invention expressly covers all combinations of the technical features belonging to the embodiments of the present invention, and the technical configurations after the combinations are expressly disclosed in this application as if the above technical configurations were separately expressly disclosed. Moreover, the present invention also expressly covers the combinations between each embodiment and their elements, and the technical configurations after the combinations are expressly disclosed in this specification. [Brief description of the drawings]

[0060] [Figure 1] 1A-1B are diagrams showing the blood pressure measurement results after 21 days of administration of plasminogen to 15-16 week-old diabetic hypertension model mice. FIG. 1A shows the systolic pressure, and FIG. 1B shows the mean pressure. As a result, after 21 days of administration, the blood pressure of the mice in the PBS-administered control group did not change significantly compared to before administration, but the systolic and mean pressures of the mice in the plasminogen-administered group were significantly lower, both of which were significantly lower than the solvent PBS-administered control group, and the difference was statistically significant (* indicates P<0.05, ** indicates P<0.01). This indicates that plasminogen can significantly reduce hypertension in 15-16 week-old diabetic mice. [Diagram 2] Figures 2A-2B are diagrams showing the blood pressure measurement results after 21 days of administration of plasminogen to 25-26 week-old diabetic hypertension model mice. Figure 2A shows the systolic pressure, and Figure 2B shows the mean pressure. As a result, after 21 days of administration, the systolic pressure of the mice in the PBS-administered control group did not change significantly compared to before administration, but the systolic pressure of the mice in the plasminogen-administered group began to decrease significantly after 7 days of administration, and was significantly lower than the solvent PBS-administered control group, and the difference was statistically significant (P = 0.019). After 14 and 21 days of administration, the difference between the two groups of mice was significant. After 21 days of administration, the mean pressure of the mice in the plasminogen-administered group was lower than the solvent PBS-administered control group, and the difference was close to significance (P = 0.09). This indicates that plasminogen can significantly reduce the high systolic pressure of 25-26 week-old diabetic mice. [Diagram 3]FIG. 3 shows the results of serum angiotensin II detection after 28 days of administration of plasminogen to 15-16 week-old diabetic hypertension model mice. As a result, after 28 days of administration of plasminogen, the serum angiotensin II level in the plasminogen-administered group was significantly lower than that in the solvent PBS-administered control group. This indicates that plasminogen can reduce the serum angiotensin II level in diabetic hypertension model mice, thereby improving hypertension. [Figure 4] Figures 4A-4B are representative photographs of H&E staining of the heart after 28 days of administration of plasminogen to 25-26 week-old diabetic hypertension model mice. Figure 4A shows the solvent PBS-administered control group, and Figure 4B shows the plasminogen-administered group. As a result, compared with the solvent PBS-administered control group (Figure 4A), the cardiomyocytes of mice in the plasminogen-administered group (Figure 4B) were more densely packed and more regularly arranged. [Diagram 5] Figures 5A-5B are representative photographs of SR staining of kidneys after administration of plasminogen to 25-26 week-old diabetic hypertension model mice for 28 days. Figure 5A shows the solvent PBS-administered control group, and Figure 5B shows the plasminogen-administered group. As a result, 28 days after plasminogen administration, the deposition of collagen fibers (marked by arrows) in the kidneys of the plasminogen-administered group was significantly less than that of the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce renal fibrosis in diabetic hypertension model mice. [Figure 6] Figure 6 shows the results of serum SOD level detection after plasminogen was administered to angiotensin II-induced hypertension model mice for 14 days. The results showed that the serum of the blank control group had a certain level of SOD, the serum SOD level of the solvent PBS-administered control group was significantly decreased, and the serum SOD level of the plasminogen-administered group was significantly higher than that of the solvent PBS-administered control group, and the difference was statistically significant (* indicates P<0.05). This indicates that plasminogen can enhance the body's ability to remove free radicals. [Figure 7]Figures 7A-7C are representative photographs of Sirius red staining of kidneys after administration of plasminogen to angiotensin II-induced hypertension model mice for 14 days. Figure 7A is the blank control group, Figure 7B is the solvent PBS-administered control group, and Figure 7C is the plasminogen-administered group. As a result, there was no obvious collagen fiber deposition in the kidneys of mice in the blank control group, and the collagen fiber deposition (marked by arrows) in the plasminogen group was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce renal fibrosis in angiotensin II-induced hypertension model mice and ameliorate renal lesions caused by hypertension. [Figure 8] Figures 8A-8C are representative photographs of Sirius red staining of the heart after administration of plasminogen to angiotensin II-induced hypertension model mice for 14 days. Figure 8A is the blank control group, Figure 8B is the solvent PBS-administered control group, and Figure 8C is the plasminogen-administered group. As a result, there was no obvious collagen fiber deposition in the hearts of mice in the blank control group, and the collagen fiber deposition (marked by arrows) in the plasminogen group was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce cardiac fibrosis in angiotensin II-induced hypertension model mice and ameliorate cardiac lesions caused by hypertension. [Figure 9] Figures 9A-9C are representative photographs of lung Sirius red staining after administration of plasminogen for 28 days to monocrotaline-induced pulmonary arterial hypertension model mice. Figure 9A is the blank control group, Figure 9B is the solvent PBS-administered control group, and Figure 9C is the plasminogen-administered group. As a result, there was essentially no collagen deposition in the lungs of mice in the blank control group, and collagen deposition in the lung tissues of mice in the plasminogen group (marked by arrows) was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce pulmonary fibrosis in monocrotaline-induced pulmonary hypertension model mice. [Figure 10]Figures 10A-10C are representative photographs of cardiac Sirius red staining after administration of plasminogen to monocrotaline-induced pulmonary arterial hypertension model mice for 28 days. Figure 10A is the blank control group, Figure 10B is the solvent PBS-administered control group, and Figure 10C is the plasminogen-administered group. As a result, there was essentially no collagen deposition in the hearts of mice in the blank control group, and collagen deposition (marked by arrows) in the hearts of mice in the plasminogen group was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce cardiac fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. [Figure 11] Figures 11A-11C are representative photographs of Sirius red staining of kidneys after administration of plasminogen for 28 days to monocrotaline-induced pulmonary arterial hypertension model mice. Figure 11A is the blank control group, Figure 11B is the solvent PBS-administered control group, and Figure 11C is the plasminogen-administered group. As a result, there was essentially no collagen deposition in the kidneys of mice in the blank control group, and collagen deposition (marked by arrows) in the kidneys of mice in the plasminogen group was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce kidney fibrosis in monocrotaline-induced pulmonary hypertension model mice. [Figure 12] Figures 12A-12C are representative photographs of Sirius red staining of livers after administration of plasminogen to monocrotaline-induced pulmonary hypertension model mice for 28 days. Figure 12A is the blank control group, Figure 12B is the solvent PBS-administered control group, and Figure 12C is the plasminogen-administered group. As a result, there was essentially no collagen deposition in the livers of mice in the blank control group, and collagen deposition (marked by arrows) in the livers of mice in the plasminogen group was significantly less than that in the solvent PBS-administered control group. This indicates that plasminogen can significantly reduce liver fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. [Figure 13]Figure 13 shows the blood pressure measurement results after plasminogen was administered to renal atrophy model mice for 14 days. As a result, the systolic pressure and mean pressure of the plasminogen administration group and the blank control group were significantly higher than that of the PBS control group, and the difference between the plasminogen administration group and the PBS control group was statistically significant (* indicates P<0.05). This indicates that plasminogen can promote the recovery of hypotension caused by renal atrophy to normal levels. [Figure 14] Figure 14 shows the measurement results of the mean pressure and contraction pressure of angiotensin II-induced hypertension model mice administered plasminogen for 5 days. As a result, the blank control group mice had a constant mean pressure and contraction pressure, the mean pressure and contraction pressure of the vehicle group mice increased significantly, the mean pressure and contraction pressure of the administration group mice were significantly lower than those of the vehicle group mice, and the difference was statistically significant (* represents P<0.05, ** represents P<0.01). This shows that plasminogen can lower the blood pressure of hypertension model mice. [Figure 15] Figure 15 shows the results of serum ACE2 level detection after 28 days of plasminogen administration to 24-25 week old diabetic mice. As a result, the serum ACE2 level of the mice in the administration group was significantly higher than that of the vehicle group, and the statistical difference was close to significance (P = 0.057). This indicates that plasminogen can promote the increase of serum ACE2 level in diabetic hypertension model mice. [Figure 16] Figure 16 shows the results of serum ACE2 level detection after 7 days of administration of plasminogen to angiotensin II-induced hypertension model mice. The results showed that there was a certain level of ACE2 in the blood of the blank control group mice, the ACE2 level in the blood of the vehicle group mice was significantly higher than that of the blank control group mice, and the ACE2 level in the blood of the administration group mice was significantly lower than that of the vehicle group mice, and the difference was statistically highly significant (** represents P<0.01). This indicates that plasminogen can promote the reduction of serum ACE2 level in AngII-induced hypertension model mice. [Figure 17] Figure 17 shows the results of serum ACE level detection after 7 days of administration of plasminogen to angiotensin II-induced hypertension model mice. The results showed that the blank control group mice had a certain level of ACE in their blood, the ACE level in the blood of the vehicle group mice was significantly higher than that of the blank control group mice, and the ACE level in the blood of the administration group mice was significantly lower than that of the vehicle group mice, and the statistical difference was close to significance (P=0.051). This indicates that plasminogen can promote the reduction of serum ACE level in AngII-induced hypertension model mice. [Figure 18] Figure 18 shows the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) during administration of the drug to a patient. As a result, the patient's systolic pressure dropped to 141 mmHg on the sixth day after administration, and on the eleventh day, the blood pressure fluctuated and became unstable (alternating between normal and abnormal), and from the twelfth day onwards, the blood pressure dropped and became normal and stable within one week. This indicates that plasminogen can lower the blood pressure of hypertensive patients. [Figure 19] Figure 19 shows the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) during the administration of the patient. As a result, the patient's blood pressure was 135 / 54 mmHg on the 13th day after administration, and was normal and stable thereafter, and basically did not require antihypertensive drugs. This indicates that plasminogen can treat hypertension. [Figure 20] Figure 20 shows the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) during medication of a patient. The results show that after administration, the diastolic pressure reached normal from less than 60 mmHg before, blood pressure during treatment was normal and stable, and after treatment, the antihypertensive drug was halved, and blood pressure was basically controlled at 130-140 / 64-76 mmHg. This shows that plasminogen can promote the return of blood pressure of hypertensive patients to normal and reduce the dosage of antihypertensive drugs. [Figure 21]21A-21B are diagrams showing the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) in the morning (21A) and evening (21B) during the patient's medication. After the fifth day of medication, the blood pressure in the morning and evening began to decrease, and the blood pressure difference became smaller. The patient reported that his blood pressure had never dropped below 140 / 75 mmHg even when taking antihypertensive drugs before, and this was the first time that it had improved. From the sixth day of medication, the morning and evening blood pressure was maintained at about 136 / 73 mmHg. From the seventh day of medication, the morning and evening blood pressure was stable, and the blood pressure was about 130 / 70 mmHg. This indicates that plasminogen can improve the patient's hypertension symptoms. [Figure 22] FIG. 22 is a diagram showing the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) during medication of a patient. As a result, blood pressure showed an upward trend after administration, and normal blood pressure appeared for the first time on the third day of medication. Blood pressure began to become normal from the ninth day of medication, and blood pressure has always remained normal since then, and blood pressure was maintained at 95 / 70 mmHg after medication was stopped. This indicates that plasminogen can promote blood pressure recovery in hypotensive patients. [Diagram 23] Figure 23 shows the detection results of systolic pressure (high pressure) and diastolic pressure (low pressure) during medication of a patient. As a result, after medication, the patient's mental state improved, and the blood pressure returned to normal the day after medication, reaching about 110 / 70 mmHg one week later. This indicates that plasminogen can promote blood pressure recovery in patients with low blood pressure. Detailed Description of the Invention

[0061] The fibrinolytic system, also called the fibrinolytic system, is a system of a series of chemicals involved in the process of fibrinolysis (fibrinolysis), mainly including plasminogen (PLG), plasmin, plasminogen activators, and fibrinolysis inhibitors. Plasminogen activators include tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). t-PA is a serine protease and is synthesized by vascular endothelial cells. t-PA activates plasminogen, a process that mainly occurs in fibrin. Urokinase-type plasminogen activator (u-PA) is produced by renal tubular epithelial cells and vascular endothelial cells and can directly activate plasminogen without the need for fibrin as a cofactor. Plasminogen (PLG) is synthesized in the liver. When blood clots, PLG is adsorbed in large quantities to the fibrin net and activated to plasmin by the action of t-PA or u-PA to promote fibrinolysis. Plasminase (PL) is a serine protease that degrades fibrin and fibrinogen, hydrolyzes various coagulation factors V, VIII, X, VII, XI, II, etc., converts plasminogen to plasmin, hydrolyzes complement, etc. Fibrinolysis inhibitors include plasminogen activator inhibitor (PAI) and α2-antithyplasmin (α2-AP). There are two main forms of PAI, PAI-1 and PAI-2, which can specifically bind to t-PA in a 1:1 ratio, thereby inactivating it and activating PLG at the same time. α2-AP is synthesized in the liver and binds to PL in a 1:1 ratio to form a complex, thereby inhibiting PL activity. FXIII covalently binds α2-AP to fibrin, thereby weakening the susceptibility of fibrin to PL. Substances that inhibit the activity of the fibrinolysis system in vivo include PAI-1, complement C1 inhibitor, α2-antiplasmin, and α2-macroglobulin.

[0062] As used herein, the term "a component of the plasminogen activation pathway" refers to a 1. Plasminogen, Lys-plasminogen, Glu-plasminogen, micro-plasminogen, delta-plasminogen, their variants or analogs; 2. Plasmin and its variants or analogues; and 3. Plasminogen activators, including, for example, tPA and uPA, as well as tPA or uPA variants and analogs that contain one or more domains of tPA or uPA, such as one or more of the kringle domain and the proteolytic domain.

[0063] The above "variants" of plasminogen, plasmin, tPA and uPA include all naturally occurring genetic variants of human and other mammalian forms of these proteins, as well as proteins having, for example, 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1 amino acid added, deleted and / or substituted and still having plasminogen activity, plasmin activity, tPA or uPA activity. For example, a "variant" of plasminogen, plasmin, tPA or uPA includes, for example, mutants of these proteins resulting from substitution of 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 conservative amino acids.

[0064] The "plasminogen variant" of the present invention covers a protein having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with sequence 2, 6, 8, 10 or 12 and still having proteolytic activity or lysine-binding activity. For example, the "plasminogen variant" of the present invention can be a protein having 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1 amino acid added, deleted and / or substituted based on sequence 2, 6, 8, 10 or 12 and still having proteolytic activity or lysine-binding activity. In particular, the plasminogen variants of the present invention include all naturally occurring genetic variants of human and other mammalian forms of these proteins, as well as mutants of these proteins obtained by conservative substitution of, for example, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acids.

[0065] The plasminogen of the present invention may be an orthologue of human plasminogen derived from a primate or rodent, or a variant which still retains proteolytic or lysine-binding activity, such as the plasminogen shown in sequences 2, 6, 8, 10 or 12, e.g., the human native plasminogen shown in sequence 2.

[0066] The above-mentioned "analogs" of plasminogen, plasmin, tPA and uPA include compounds that provide substantially the same effect as plasminogen, plasmin, tPA or uPA, respectively.

[0067] The above "variants" and "analogs" of plasminogen, plasmin, tPA and uPA cover "variants" and "analogs" of plasminogen, plasmin, tPA and uPA that contain one or more domains (e.g., one or more kringle domains and a proteolytic domain). For example, "variants" and "analogs" of plasminogen cover plasminogen variants and analogs, such as mini-plasminogen, that contain one or more plasmin domains (e.g., one or more kringle domains and a proteolytic domain). "Variants" and "analogs" of plasmin cover plasmin "variants" and "analogs" such as mini-plasmin and delta-plasmin that contain one or more plasmin domains (e.g., one or more kringle domains and a proteolytic domain).

[0068] Whether the above-mentioned "variants" or "analogs" of plasminogen, plasmin, tPA or uPA have the activity of plasminogen, plasmin, tPA or uPA, respectively, or whether they exert substantially the same effect as plasminogen, plasmin, tPA or uPA, respectively, can be measured by the level of activated plasmin activity using methods known in the art, such as enzymography, ELISA (enzyme-linked immunosorbent assay) and FACS (fluorescence-activated cell sorting). For example, the measurement can be performed with reference to the methods described in the following documents:Ny,A.,Leonardsson,G.,Hagglund,A.C,Hagglof,P.,Ploplis,V.A.,Carmeliet,P. and Ny,T. (1999). Ovulation inplasminogen-deficient mice. Endocrinology 140,5030-5035;Silverstein RL, Leung LL, Harpel PC, Nachman RL (November 1984). ”Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator”. J. Clin. Invest. 74 (5): 1625-33;Gravanis I, Tsirka SE (February 2008). ”Tissue-type plasminogen activator as a therapeutic target in stroke”. Expert Opinion on Therapeutic Targets. 12 (2): 159-70;Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR (Aug 1989). ”Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo”. Blood. 74 (2): 722-8。

[0069] In some embodiments of the present invention, the "component of the plasminogen activation pathway" of the present invention is a plasminogen selected from Glu-plasminogen, Lys-plasminogen, miniplasminogen, microplasminogen, δ-plasminogen, or a variant thereof that retains proteolytic or lysine-binding activity. In some embodiments, the plasminogen is natural or synthetic human plasminogen, or a conservative mutant or fragment thereof that still retains proteolytic or lysine-binding activity. In some embodiments, the plasminogen is an orthologue of human plasminogen from a primate or rodent, or a conservative mutant or fragment thereof that still retains proteolytic or lysine-binding activity. In some embodiments, the amino acid sequence of the plasminogen is set forth in sequence 2, 6, 8, 10, or 12. In some embodiments, the plasminogen is human native plasminogen. In some embodiments, the plasminogen is human native plasminogen set forth in sequence 2.

[0070] "A compound capable of directly activating plasminogen or indirectly activating plasminogen by activating an upstream component of the plasminogen activation pathway" refers to any compound capable of directly activating plasminogen or indirectly activating plasminogen by activating an upstream component of the plasminogen activation pathway, including, for example, tPA, uPA, streptokinase, saruplase, alteplase, reteplase, tenecteplase, anistreplase, monteplase, lanoteplase, pamiteplase, and staphylokinase.

[0071] The "antagonist of fibrinolysis inhibitors" of the present invention is a compound that antagonizes, weakens, blocks, or prevents the action of fibrinolysis inhibitors, such as PAI-1, complement C1 inhibitor, α2-antiplasmin, and α2-macroglobulin. Said antagonists are antibodies to PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin, or for example antisense RNA or miniRNA that blocks or downregulates the expression of PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin, or compounds that occupy the binding site of PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin but do not have the function of PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin, or compounds that block the binding and / or activity domains of PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin.

[0072] Plasmin is an important component of the plasminogen activation system (PA system). It is a broad-spectrum protease that can hydrolyze several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycans. Plasmin can also activate some pro-matrix metalloproteinases (pro-MMPs) to become active matrix metalloproteinases (MMPs). Thus, plasmin is an important upstream regulator of extracellular proteolysis. Plasmin is formed by proteolysis of two physiological PAs: tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). Plasminogen is present at relatively high relative levels in plasma and other body fluids, and traditionally, it has been believed that the regulation of the PA system is mainly achieved by the synthesis and activity levels of PA. The synthesis of the components of the PA system is tightly regulated by different factors, such as hormones, growth factors, and cytokines. In addition, there are specific physiological inhibitors of plasmin and PAs. The main inhibitor of plasmin is α2-antiplasmin. The activity of PAs is simultaneously inhibited by plasminogen activator inhibitor-1 (PAI-1) of uPA and tPA, and is regulated by plasminogen activator inhibitor-2 (PAI-2), which mainly inhibits uPA. Some cells have a uPA-specific cell surface receptor (uPAR) with direct hydrolytic activity.

[0073] Plasminogen is a single-chain glycoprotein consisting of 791 amino acids with a molecular weight of approximately 92 kDa. Plasminogen is synthesized mainly in the liver and is present in large amounts in extracellular fluids. The plasminogen content in plasma is approximately 2 μM. Thus, plasminogen is a large potential source of proteolytic activity in tissues and body fluids. There are two molecular forms of plasminogen: glutamate-plasminogen (Glu-plasminogen) and lysine-plasminogen (Lys-plasminogen). The naturally secreted and undegraded form of plasminogen has one amino-terminal (N-terminal) glutamic acid and is therefore called glutamate-plasminogen. However, in the presence of plasmin, glutamate-plasminogen is hydrolyzed to lysine-plasminogen at Lys76-Lys77. Compared to glutamate-plasminogen, lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate. The Arg560-Val561 peptide bond of the two forms of plasminogen is cleaved by uPA or tPA, resulting in the formation of the disulfide-linked double-chain protease plasmin. The amino-terminal part of plasminogen contains five homologous tricycles, the so-called kringles, and the carboxyl-terminal part contains the protease domain. Some kringles contain a lysine-binding site that mediates the specific interaction of plasminogen with fibrin and its inhibitor α2-AP. The most recently discovered fibrin-plasminogen fragment of 38 kDa, kringlel-4, is a potent inhibitor of angiogenesis. This fragment, named angiostatin, is generated from several protease-hydrolyzed plasminogens.

[0074] The main substrate for plasmin is fibrin, and fibrin lysis is a key factor in preventing the formation of pathological thrombi. [Plasmin also has substrate specificity for several components of the ECM, including laminin, fibronectin, proteoglycans, and gelatin, indicating that plasmin plays an important role in ECM remodeling. Indirectly, plasmin also degrades other components of the ECM by converting several protease precursors, including MMP-1, MMP-2, MMP-3, and MMP-9, into active proteases. Therefore, it may be proposed that plasmin is an important upstream regulator of extracellular protein hydrolysis. Plasmin also has the ability to activate several latent forms of growth factors. In vitro, plasmin can also hydrolyze components of the complement system to release chemotactic complement fragments.

[0075] "Plasmin" is a very important enzyme present in blood, which hydrolyzes fibrin clots into fibrin degradation products and D-dimers.

[0076] "Plasminogen" is the proenzyme form of plasmin, which, based on the sequence in swiss prot, is calculated as the amino acid sequence of natural human plasminogen including the signal peptide (Sequence 4), and consists of 810 amino acids, has a molecular weight of about 90 kD, is synthesized mainly in the liver, and is a glycoprotein that can circulate in the blood, and the cDNA sequence encoding said amino acid sequence is as shown in Sequence 3. Full-sized plasminogen contains seven domains: a serine protease domain located at the C-terminus, a Pan Apple (PAp) domain located at the N-terminus, and five Kringle domains (Kringle 1-5). With reference to the sequence in swiss prot, the signal peptide comprises residues Met1-Gly19, PAp comprises residues Glu20-Val98, Kringle1 comprises residues Cys103-Cys181, Kringle2 comprises residues Glu184-Cys262, Kringle3 comprises residues Cys275-Cys352, Kringle4 comprises residues Cys377-Cys454, and Kringle5 comprises residues Cys481-Cys560. According to the NCBI data, the serine protease domain comprises residues Val581-Arg804.

[0077] Glu-plasminogen is a natural full-sized human plasminogen, and consists of 791 amino acids (not including a signal peptide consisting of 19 amino acids). The cDNA sequence encoding this sequence is as shown in sequence 1, and its amino acid sequence is as shown in sequence 2. In the body, Lys-plasminogen is formed by hydrolysis at the 76th-77th amino acid positions of Glu-plasminogen, and is, for example, as shown in sequence 6, and the cDNA sequence encoding this amino acid sequence is as shown in sequence 5. Delta-plasminogen (δ-plasminogen) is a fragment of full-sized plasminogen lacking the Kringle2-Kringle5 structure, and contains only Kringle1 and a serine protease domain (also called the protease domain (PD)). There is a literature that reports the amino acid sequence of δ-plasminogen (sequence 8), and the cDNA sequence encoding this amino acid sequence is, for example, sequence 7. Mini-plasminogen consists of Kringle5 and serine protease domains, and the literature reports residues Val443-Asn791 (starting with the Glu residue of the Glu-plasminogen sequence without the signal peptide), and its amino acid sequence is as shown in sequence 10, and the cDNA sequence encoding this amino acid sequence is as shown in sequence 9. However, literature reports that microplasminogen only contains a serine protease domain, and its amino acid sequence is residues Ala543-Asn791 (the Glu residue of the Glu-plasminogen sequence without the signal peptide is the starting amino acid), and patent document CN102154253A discloses that it contains residues Lys531-Asn791 (the Glu residue of the Glu-plasminogen sequence without the signal peptide is the starting amino acid), and in this patent application, the sequence of microplasminogen can be referred to patent document CN102154253A, and its amino acid sequence is as shown in sequence 12, and the cDNA sequence encoding the amino acid sequence is as shown in sequence 11.

[0078] The structure of full-length plasminogen is also described in a paper by Aisina et al. (Aisina RB, Mukhametova L I. Structure and function of plasminogen / plasmin system[J]. Russian Journal of Bioorganic Chemistry, 2014, 40(6):590-605). According to the above mentioned article by Aisina et al., plasminogen contains Kringle 1, 2, 3, 4, 5 domains and a serine protease domain (also called protease domain (PD)), Kringles are responsible for binding plasminogen to low and high molecular weight ligands (i.e., lysine binding activity), which results in the conversion of plasminogen to a more open configuration and makes it more accessible to activation, and the protease domain (PD) is residues Val562-Asn791, and tPA and UPA specifically cleave the Arg561-Val562 activating bond of plasminogen, thereby allowing plasminogen to form plasmin. Thus, the protease domain (PD) is the region that confers the proteolytic activity of plasminogen.

[0079] In the present invention, "plasmin", "fibrin plasmin", and "fibrous protein plasmin" can be used interchangeably and have the same meaning. "Plasminogen", "fibrin plasminogen", and "fibrous protein plasminogen" can be used interchangeably and have the same meaning.

[0080] In this application, the "deficiency" of plasminogen refers to the content or activity of plasminogen in the subject's body being lower than that of a normal person and being sufficiently low to affect the normal physiological function of the subject. The "deficiency" of plasminogen means that the content or activity of plasminogen in the subject's body is obviously lower than that of a normal person, the activity or expression is extremely low, and the normal physiological function can only be maintained by external supply.

[0081] Those skilled in the art can understand as follows. All technical configurations of plasminogen in the present invention can be applied to plasmin, so the technical configurations described in the present invention cover plasminogen and plasmin. In the circulation process, plasminogen is in a closed inactive conformation, but when it binds to a thrombus or cell surface, it becomes active plasmin with an open conformation under the mediation of a plasminogen activator (PA). The active plasmin further hydrolyzes fibrin clots into fibrin degradation products and D-dimers, thereby dissolving the thrombus. Among them, the PAp domain of plasminogen is an important epitope that makes plasminogen in an inactive closed conformation, but the KR domain can bind to lysine residues on receptors and substrates. There are already several types of enzymes known as plasminogen activators, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and coagulation factor XII (Hageman factor), etc.

[0082] "Plasminogen active fragment" refers to an active fragment that binds to lysine in the target sequence of a substrate (lysine binding activity), or an active fragment that exerts a proteolytic function (proteolytic activity), or a fragment that has both proteolytic activity and lysine binding activity. The technical configuration of the present invention related to plasminogen includes a technical configuration in which plasminogen is replaced with a plasminogen active fragment. In some embodiments, the plasminogen active fragment of the present invention comprises the serine protease domain of plasminogen or consists of the serine protease domain of plasminogen, and preferably, the plasminogen active fragment of the present invention comprises sequence 14 or comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identity with sequence 14, or consists of an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identity with sequence 14. In some embodiments, the plasminogen active fragments of the present invention comprise one or more domains selected from Kringle 1, Kringle 2, Kringle 3, Kringle 4, and Kringle 5, or consist of one or more domains selected from Kringle 1, Kringle 2, Kringle 3, Kringle 4, and Kringle 5. In some embodiments, the plasminogen of the present invention comprises a protein comprising the above plasminogen active fragments.

[0083] At present, the methods for measuring plasminogen and its activity in blood include tissue plasminogen activator activity (t-PAA), plasma tissue plasminogen activator antigen (t-PAAg), plasma tissue plasminogen activity (plgA), plasma tissue plasminogen antigen (plgAg), plasma tissue plasminogen activator inhibitor activity, plasma tissue plasminogen activator inhibitor antigen, and plasma plasmin-antiplasmin complex (PAP). The most common method is the chromogenic substrate method: streptokinase (SK) and luminescent substrate are added to the plasma of the subject, and the PLG in the subject's plasma becomes PLM under the action of SK, which acts on the luminescent substrate, and then measured by a spectrophotometer, and the increase in absorbance is directly proportional to the activity of plasminogen. In addition, immunochemical methods, gel electrophoresis, immunoturbidimetry, radial immunodiffusion, etc. can also be used to measure plasminogen activity in blood.

[0084] "Ortholog" refers to a homologue between different species, including both protein and DNA homologues, also called a direct lineage gene. It specifically refers to a protein or gene that is evolved from the same ancestral gene between different species. The plasminogen of the present invention includes human native plasminogen, and further includes orthologs or orthologs of plasminogens with plasminogen activity derived from different species.

[0085] A "conservative substitution variant" is one in which a specified amino acid residue is modified but does not change the overall conformation and function of a protein or enzyme, including but not limited to those that substitute an amino acid in the amino acid sequence of a parent protein with an amino acid of similar properties (e.g., acidic, alkaline, hydrophobic, etc.). Amino acids with similar properties are known. For example, arginine, histidine, and lysine are hydrophilic alkaline amino acids and can be substituted for each other. Similarly, isoleucine is a hydrophobic amino acid and can be substituted by leucine, methionine, or valine. Therefore, the similarity of two proteins or amino acid sequences with similar functions may vary. For example, they have a similarity (identity) of 70% to 99% based on the MEGALIGN algorithm. "Conservative substitution variant" further includes polypeptides or enzymes with an amino acid identity of 60% or more based on the BLAST or FASTA algorithm, preferably 75% or more, most preferably 85% or more, and most preferably 90% or more, and have the same or essentially similar properties or functions compared to the natural or parent protein or enzyme.

[0086] "Isolated" plasminogen is plasminogen protein that has been separated and / or recovered from its natural environment. In some embodiments, the plasminogen is (1) purified to greater than 90%, greater than 95%, or greater than 98% purity (by weight), e.g., greater than 99% (by weight), as determined by the Lowry method; (2) purified to at least 15 residues of N-terminal or internal amino acid sequence as determined by a spinning cup sequencer; or (3) purified to homogeneity, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing or non-reducing conditions with Coomassie brilliant blue or silver staining. Isolated plasminogen includes plasminogen produced from recombinant cells by bioengineering techniques and separated by at least one further purification step.

[0087] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length, including genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derived amino acids, and polypeptides having modified peptide backbones. The terms also include fusion proteins, including, but not limited to, fusion proteins with heterologous amino acid sequences, fusions containing leader sequences of heterologous and homologous origin (with or without an N-terminal methionine residue); and the like.

[0088] The definition of "percentage (%) amino acid sequence identity" of a reference peptide sequence is the percentage of amino acid residues in a candidate sequence that are the same as those in the reference polypeptide sequence, after introducing gaps as necessary to achieve the maximum percentage sequence identity, without considering any conservative substitutions as part of the sequence identity. Comparisons aimed at determining percentage amino acid sequence identity can be achieved by a variety of methods within the skill of the art, for example by publicly available computer software, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm that achieves maximum comparison requirements for the full size of the sequences to be compared. However, for the purposes of the present invention, the percentage amino acid sequence identity is obtained by the sequence comparison computer software ALIGN-2.

[0089] When comparing amino acid sequences by using ALIGN-2, the % amino acid sequence identity of a given amino acid sequence A to a given amino acid sequence B (or alternatively, a given amino acid sequence A that has or contains a certain % amino acid sequence identity to, with, or for a given amino acid sequence B) is calculated as follows: Fraction X / Y×100

[0090] where X is the number of amino acid residues that the sequence alignment program ALIGN-2 evaluates as identical and matching in its alignment of A and B, and Y is the total number of amino acid residues in B. It should be understood as follows: if the length of amino acid sequence A and the length of amino acid sequence B are not equal, then the % amino acid sequence identity of A to B will be different from the % amino acid sequence identity of B to A. Unless otherwise stated, all % amino acid sequence identity values ​​used in this text are as described in the previous paragraph and are obtained by the ALIGN-2 computer program.

[0091] As used herein, the term "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be completely or partially preventing the onset or development of a disease or its symptoms, or partially or completely reducing the disease and / or its symptoms, and / or partially or completely curing the disease and / or its symptoms. It also includes: (a) preventing a disease from occurring in a subject, where the subject has the causative agent for the disease but has not been diagnosed with the disease; (b) inhibiting the disease or inhibiting its formation; and (c) attenuating the disease and / or its symptoms, i.e., reducing the disease and / or its symptoms.

[0092] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to mammals, including, but not limited to, murines (rats, mice), non-human primates, humans, dogs, cats, ungulates (e.g., horses, cows, sheep, pigs, goats), and the like.

[0093] A "therapeutically effective amount" or "effective amount" is an amount of a component of the plasminogen activation pathway or its related compound (e.g., plasminogen) that is capable of achieving said prevention and / or treatment of a disease when administered to a mammal or other subject and used to treat the disease. A "therapeutically effective amount" will vary according to the component of the plasminogen activation pathway or its related compound (e.g., plasminogen) used, the severity of the disease and / or symptoms, and the age, weight, etc., of the subject to be treated.

[0094] In this application, "promoting repair of damaged tissues and organs" refers to promoting the repair of the structure and function of damaged tissues and organs in order to restore as much normal integrity and function as possible to the anatomical structure of the damaged tissues and organs.

[0095] In this specification, "high blood pressure" or "hypertension" refers to a state in which the systemic arterial pressure is higher than normal. According to the 1999 World Health Organization / International Society of Hypertension treatment guidelines, the diagnostic criteria for hypertension are systolic pressure of 18.7 Kpa (140 mmHg) or higher or diastolic pressure of 12.0 Kpa (90 mmHg) or higher. "Hypotension" or "hypotension" refers to a state in which the systemic arterial pressure is lower than normal. There is no unified standard for diagnosing hypotension. In general, when the systolic / diastolic pressure of the upper limb arteries of an adult is less than 12 / 8 kPa (90 / 60 mmHg), respectively, it is considered to be hypotension. The diagnostic criteria for the blood pressure indicators of "high blood pressure" or "hypertension" and "hypotension" or "hypotension" may refer to the specific provisions of the diagnostic manual of each country.

[0096] In this application, treating a subject with "high blood pressure" or "hypertension" includes "lowering" or "reducing" high blood pressure in a subject suffering from "high blood pressure" or "hypertension", where "lowering" or "reducing" refers to lowering the subject's blood pressure compared to when the drug is not administered or compared to the subject's blood pressure before administration, e.g., normalizing, approaching normal, or returning the subject's blood pressure to a normal level. Similarly, in this application, treating a subject with "low blood pressure" or "hypotension" includes "increasing" low blood pressure in a subject suffering from "low blood pressure" or "hypotension". The "increasing" refers to increasing the subject's blood pressure compared to an unadministered control or compared to the subject's blood pressure before administration, e.g., normalizing, approaching normal, or returning the subject's blood pressure to a normal level.

[0097] "Complication" means that one disease causes the occurrence of another disease or condition during the course of its development, the latter being a complication of the former, i.e., the occurrence of the latter disease is caused by the former disease, or that during the diagnosis and treatment of a disease, a patient develops one or more other diseases related to the disease.

[0098] "Hypertensive complications" refers to complications caused by hypertension, including damage to the heart, brain, lungs, liver, kidneys, or blood vessels caused by hypertension. Complications of heart damage caused by hypertension include left ventricular hypertrophy, angina pectoris, myocardial infarction, heart failure, etc. Complications of brain tissue damage caused by hypertension include cerebral hemorrhage, cerebral thrombosis, cerebral infarction, hemorrhagic stroke, ischemic stroke, hypertensive encephalopathy, etc. Renal damage caused by hypertension includes slowly progressive small arteriosclerosis, malignant small arteriosclerosis, chronic renal failure, hypertensive nephropathy, renal failure, uremia, etc. The most common complication of hypertension is cerebrovascular disease, followed by hypertensive heart disease, heart failure, and renal failure. A rare but serious complication is aortic dissection aneurysm.

[0099] "Hypotension complications" refers to complications caused by low blood pressure. Common complications of low blood pressure are mainly caused by insufficient perfusion of vital organs. For example, insufficient blood supply to the brain often causes symptoms such as tinnitus and dizziness, and in severe cases may be complicated by cerebral infarction. Insufficient blood supply to the heart mainly causes symptoms such as palpitations, shortness of breath, and chest tightness. Insufficient blood supply to the kidneys most often manifests as oliguria, proteinuria, and in severe cases, renal failure such as anuria.

[0100] Preparation of the Plasminogen of the Invention For therapeutic use, plasminogen may be isolated and purified from nature or may be synthesized by standard chemical peptide synthesis techniques. When polypeptides are synthesized by chemical methods, the synthesis may be performed in liquid phase or solid phase. Solid phase polypeptide synthesis (SPPS), in which the C-terminal amino acid of the sequence is attached to an insoluble support and the remaining amino acids in the sequence are added in order, is suitable for the chemical synthesis of plasminogen. Various forms of SPPS, e.g., Fmoc and Boc, can be used to synthesize plasminogen. The techniques used for solid-phase synthesis are described in: Barany and Solid-Phase Peptide Synthesis; pages 3-284, The Peptides: Analysis, Synthesis, Biology. Volume 2: Special Methods in Peptide Synthesis, Part A., Merrifield, et al. J. Am. Chem. Soc., 85: 2149-2156 (1963); Stewart et al., Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, Ill. (1984); and Ganesan A. 2006 Mini Rev. Med Chem. 6: 3-10 and Camarero JA et al. 2005 Protein Pept Lett. 12: 723-8. Briefly, small insoluble porous beads are treated with functional units on which the peptide chain is built. After repeated coupling / deprotection cycles, the free N-terminal amine of the attached solid phase is coupled with a single N-protected amino acid unit, which is then deprotected to expose a new N-terminal amine for linking with another amino acid, and the peptide remains immobilized on the solid phase before it is excised.

[0101] The plasminogen of the present invention is produced by standard recombinant methods. For example, a nucleic acid encoding plasminogen is inserted into an expression vector and operably linked to control sequences in the expression vector. Expression control sequences include, but are not limited to, a promoter (e.g., a naturally associated promoter or a heterologous promoter), a signal sequence, an enhancer element, and a transcription termination sequence. Control of expression can be a eukaryotic promoter system in a vector that is transformed or transfected into a eukaryotic host cell (e.g., COS or CHO cells). Once the vector is introduced into a suitable host, the host is maintained under conditions suitable for high level expression of the nucleotide sequence and for collection and purification of the plasminogen.

[0102] Suitable expression vectors usually replicate in the host cell either free or as an integrated part of the host cell chromosomal DNA. Usually, expression vectors contain a selection marker (e.g., ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance) which is useful for detecting those cells which have been transformed in vitro with the desired DNA sequence.

[0103] Escherichia coli is an example of a prokaryotic host cell for cloning a polynucleotide encoding a compound of interest. Other suitable microbial hosts include bacilli, such as Bacillus subtilis and other Enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species. In these prokaryotic hosts, expression vectors can be generated, which usually contain expression control sequences (e.g., origins of replication) compatible with the host cell. There are also many known promoters, such as the lactose promoter system, the tryptophan (trp) promoter system, the β-lactamase promoter system, or the phage lambda-derived promoter system. Promoters generally control expression and may further include ribosome binding site sequences, etc., to initiate transcription and translation when controlling gene sequences, as needed.

[0104] Other microorganisms, such as yeast, can also be used for expression. Yeast (e.g., Saccharomyces (S. cerevisiae) and Pichia are examples of suitable yeast host cells, of which suitable carriers include expression control sequences (e.g., promoters), origins of replication, termination sequences, etc., as necessary. Exemplary promoters include 3-phosphoglycerate kinase and other glycolytic enzymes. Inducible yeast promoters include, inter alia, promoters for alcohol dehydrogenase, isocytochrome C, and enzymes for maltose and galactose utilization.

[0105] In addition to microorganisms, mammalian cells (e.g., mammalian cells cultured in in vitro cell culture) can also be used to express and produce the plasminogen (e.g., a polynucleotide encoding plasminogen) of the present invention. See, e.g., Winnacker, From Genes to Clones, VCH Publishers, NY, NY (1987). Suitable mammalian host cells include CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, and transformed B cells or hybridomas. Expression vectors for use in these cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (Queen et al., Immunol. Rev. 89:49 (1986)), and required processing information sites, such as ribosome binding sites, RNA cleavage sites, polyadenosine oxidation sites, and transcription terminator sequences. Examples of suitable expression control sequences are promoters derived from rabbit immunoglobulin genes, SV40, adenovirus, bovine papilloma virus, cytomegalovirus, and the like. See Co et al., J. Immunol. 148:1149 (1992).

[0106] Once synthesized (chemically or recombinantly), the plasminogen according to the invention can be purified by standard procedures in the art, such as ammonium sulfate precipitation, affinity columns, column chromatography, high performance liquid chromatography (HPLC), gel electrophoresis, etc. The plasminogen is essentially pure, e.g., at least about 80% to 85% pure, at least about 85%-90% pure, at least about 90%-95% pure, or 98%-99% pure or even more pure, e.g., free of contaminants, such as cell debris, large molecules other than plasminogen, etc.

[0107] Drug combinations Plasminogen of the desired purity is mixed with pharmaceutical carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 16th ed., Osol, A. ed. (1980)) as required to form a lyophilized formulation or aqueous solution to obtain the therapeutic combination. Acceptable carriers, excipients, and stabilizers are non-toxic to subjects at the required dosages and concentrations, and further include buffers such as phosphates, citrates, and other organic acids. Antioxidants include ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethylenediamine chloride; benzalkonium chloride). chloride), benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parahydroxybenzoic acid esters, such as methyl or propyl parahydroxybenzoic acid ester; pyrocatechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol; low molecular weight polypeptides (those having less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates include glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, fucose or sorbitol; salt forming counterions, such as sodium; metal complexes (such as zinc-protein complexes); and / or non-ionic surfactants, such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG).

[0108] The combination preparation of the present invention may contain one or more active compounds as required for the specific condition requiring treatment, preferably with complementary activities and no side effects, such as antihypertensives, antiarrhythmics, and antidiabetics.

[0109] The plasminogen of the present invention can be encapsulated in microcapsules made, for example, by aggregation techniques or interfacial polymerization, can be incorporated, for example, into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or can be incorporated into hydroxymethylcellulose or gel microcapsules and poly(methyl methacrylate) microcapsules in crude emulsions. These techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0110] The plasminogen of the present invention to be administered internally must be sterile, which is readily accomplished by filtration through sterile filtration membranes, prior to or after lyophilization and recombination.

[0111] The plasminogen of the present invention can be prepared in sustained release formulations. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers having defined shapes and containing the glycoprotein, such as membranes or microcapsules. Examples of sustained release matrices include polyesters, aqueous gels (e.g., poly(2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15:167-277 (1981); Langer, Chem. Tech., 12:98-105 (1982)) or poly(vinyl alcohol), polylactide (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and ethyl-L-glutamic acid (Sidman, et al., Biopolymers 22:547 (1983)), non-degradable ethylene-vinyl acetate (Langer, et al., same source as above), or degradable lactic acid-hydroxyacetic acid copolymers, e.g., Lupron. Depot™ (injectable microspheres composed of lactic acid-hydroxyacetic acid copolymer and leuprolide acetate), and poly D-(-)-3-hydroxybutyrate. Polymers such as ethylene-ethyl acetate and lactic acid-hydroxyacetic acid can release molecules sustainedly for over 100 days, but some aqueous gels release proteins for a shorter period of time. Rational strategies can be designed to stabilize proteins depending on the mechanism involved. For example, if the aggregation mechanism is the exchange of sulfur disulfide bonds to form intermolecular SS bonds, stabilization can be achieved by modifying sulfhydryl residues, freeze-drying from acidic solutions, controlling humidity, using appropriate additives, and developing specific polymer matrix compositions.

[0112] Dosage and dosage Administration of the pharmaceutical compositions of the present invention can be achieved by different modes, such as nasal inhalation, aerosol inhalation, nose drops, eye drops, ear drops, intravenous, intraperitoneal, subcutaneous, intracranial, intrathecal, intraarterial (e.g., via the carotid artery), intrarectal, intramuscular, and intrarectal administration.

[0113] Preparations for use in parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solutions, Ringer's dextrose, dextrose and sodium chloride, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolytic replenishers, and the like. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, inert gases, and the like.

[0114] A medical practitioner may determine a dosage regimen based on various clinical factors. For example, as is known in the medical arts, the dosage regimen for any given patient is determined by several factors, including the patient's body type, body surface area, age, the specific compound being administered, sex, frequency and route of administration, overall health, and other drugs being administered at the same time. The dosage range of the plasminogen-containing pharmaceutical composition of the present invention may be, for example, about 0.0001-2000 mg / kg of subject body weight daily, or about 0.001-500 mg / kg (e.g., 0.02 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 10 mg / kg, 50 mg / kg, etc.). For example, the dosage may be 1 mg / kg body weight or 50 mg / kg body weight or in the range of 1-50 mg / kg, or at least 1 mg / kg. Doses higher or lower than this illustrative range are also covered, particularly when the above factors are taken into account. Intermediate doses within the above range are also within the scope of the present invention. Subjects may receive such doses daily, every other day, weekly, or according to any schedule determined by empirical analysis. An exemplary dose schedule is 0.01-100 mg / kg for several consecutive days. During the administration of the drug of the present invention, it is necessary to evaluate the therapeutic effect and safety in real time.

[0115] Product or drug kit One embodiment of the present invention relates to an article of manufacture or drug kit comprising the plasminogen or plasmin of the present invention that can be used to treat hypertension and related conditions. The article of manufacture preferably includes a container, a label, or a protocol. Suitable containers are bottles, vials, syringes, and the like. The containers can be made of a variety of materials, such as glass or plastic. The container contains a composition, the composition is effective to treat a disease or condition of the present invention, and has a sterile inlet (e.g., the container is an intravenous infusion pack or vial and includes a stopper that can be pierced by a hypodermic needle). At least one activator in the composition is plasminogen / plasmin. A label on or attached to the container describes the composition as being used to treat hypertension and related conditions of the present invention. The article of manufacture may further include a second container containing a pharmaceutical buffer, such as phosphate buffered saline, Ringer's solution, and glucose solution. It may further include other materials as may be required from a commercial and user perspective, i.e., other buffers, diluents, filters, needles, and syringes. The article of manufacture also includes a protocol with instructions, for example, instructing a user of the composition to administer the plasminogen composition and other medications associated with treating a disease to a patient. EXAMPLES

[0116] All plasminogens used in the following examples are human plasminogens, derived from the plasma of human donors, and are described in the following publications: Kenneth C Robbins, Louis Summaria, David Elwyn et al. Further Studies on the Purification and Characterization of Human Plasminogen and Plasmin. Journal of Biological Chemistry, 1965, 240(1):541-550; Summaria L, Spitz F, Arzadon L et al. Isolation and characterization of the affinity chromatography forms of human Glu- and Lys-plasminogens and plasmins. J Biol Chem. 1976 Jun 25; 251(12):3693-9; HAGAN JJ, ABLONDI FB, DE RENZO EC. Purification and biochemical properties of human plasminogen. J Biol Chem. 1960 Based on the method described in Apr;235:1005-10, the process was optimized and purified from human donor plasma, in which human Lys-plasminogen (Lys-plasminogen) and Glu-plasminogen (Glu-plasminogen) were more than 98%.

[0117] In the following Examples 1 to 5, db / db mice (purchased from Nanjing Institute of Biological Medicine, strain name BKS.Cg-Dock7m+ / -Leprdb / JNju) were used as a hypertension model to study the effect of plasminogen on hypertension. Some literature has reported that db / db mice spontaneously developed hypertension at 11 to 14 weeks and that blood pressure continued to increase with age. [24,25] . Example 1

[0118] Example 1 relates to plasminogen reducing hypertension in 15-16 week old diabetic mice. Twelve db / db male mice aged 15-16 weeks were taken, and their basal blood pressure was measured after their weight was measured on the day before administration. They were randomly divided into two groups, a PBS-treated control group and a plasminogen-treated group, with six mice in each group, according to their blood pressure. Plasminogen was administered to the mice in the plasminogen-treated group at 2 mg / 0.2 ml / mouse / day via tail vein injection, and the same volume (same amount) of PBS solution was administered to the mice in the PBS-treated control group via tail vein injection for 21 consecutive days. The day administration began was set as day 1, and blood pressure was measured on days 0, 8, 15, and 22, five consecutive measurements were taken per mouse, and the systolic pressure and mean pressure were recorded for each measurement. The systolic pressure and mean blood pressure are the average values ​​of the systolic pressure and mean pressure data obtained from five measurements, respectively. The mean blood pressure is calculated as 1 / 3 of the systolic pressure + 2 / 3 of the diastolic pressure. The blood pressure of the mice was measured using a non-invasive blood pressure monitor (MRBP-M01, IITC Life science). As a result, after 21 days of administration, the blood pressure of the mice in the PBS-administered control group did not change significantly compared to before administration, but the systolic pressure (Figure 1A) and mean pressure (Figure 1B) of the mice in the plasminogen-administered group were significantly lower, both of which were significantly lower than the control group administered with the solvent PBS, and the difference was statistically significant (* indicates P<0.05, ** indicates P<0.01). This indicates that plasminogen can significantly reduce hypertension in 15-16 week-old diabetic mice. Example 2

[0119] Example 2 relates to plasminogen reducing hypertension in 25-26 week old diabetic mice. Thirteen db / db male mice aged 25-26 weeks were taken, and their basal blood pressure was measured after weight measurement on the day before administration. They were randomly divided into two groups according to their blood pressure, six in the control group administered with PBS and seven in the plasminogen group. Plasminogen was administered to the mice in the plasminogen group at 2 mg / 0.2 ml / mouse / day by tail vein injection, and the same amount of PBS solution was administered to the mice in the control group administered with PBS by tail vein injection for 21 consecutive days. The day administration began was set as day 1, and blood pressure was measured on days 0, 8, 15, and 22. Each mouse was measured five times in a row, and the systolic pressure and mean pressure were recorded for each measurement. The systolic pressure and mean blood pressure are the average values ​​of the systolic pressure and mean pressure data obtained from five measurements, respectively. The blood pressure of the mice was measured using a non-invasive blood pressure monitor (MRBP-M01, IITC Life science). As a result, after 21 days of administration, the contractile pressure of the mice in the PBS-administered control group did not change significantly compared to before administration, but the contractile pressure of the mice in the plasminogen-administered group began to decrease significantly after 7 days of administration, and was significantly lower than that of the solvent PBS-administered control group, and the difference was statistically significant (P = 0.019). After 14 and 21 days of administration, the difference between the two groups of mice was significant (Figure 2A). After 21 days of administration, the average pressure of the mice in the plasminogen-administered group was lower than that of the solvent PBS-administered control group, and the difference was close to significance (P = 0.09) (Figure 2B). This indicates that plasminogen can significantly reduce the high contractile pressure of diabetic mice aged 25 to 26 weeks. Example 3

[0120] Example 3 relates to the effect of plasminogen on lowering serum angiotensin II levels in diabetic hypertension model mice. Twelve db / db male mice aged 15-16 weeks were taken, and their basal blood pressure was measured after weight measurement on the day before administration. They were randomly divided into two groups, a solvent PBS-administered control group and a plasminogen-administered group, with six mice in each group, according to their blood pressure. Plasminogen was administered to the mice in the plasminogen-administered group at 2 mg / 0.2 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the solvent PBS-administered control group via tail vein injection for 28 consecutive days. On the 29th day, the eyes were removed, blood was collected, and the supernatant was obtained by centrifugation. Serum angiotensin II levels were detected according to the instructions of the angiotensin II detection kit (manufacturer: Wuhan Huamei Biotechnology Co., Ltd., catalog number: CSB-E04495m). As a result, after 28 days of plasminogen administration, the serum angiotensin II level in the plasminogen-administered group was significantly lower than that in the control group administered with the solvent PBS (Figure 3). This indicates that plasminogen can reduce the serum angiotensin II level in diabetic hypertension model mice, thereby improving hypertension. Example 4

[0121] Example 4 relates to the promotion of repair of cardiac damage in diabetic hypertension model mice by plasminogen. Thirteen db / db male mice aged 25-26 weeks were taken, and their basal blood pressure was measured after weight measurement the day before administration. They were randomly divided into two groups according to their blood pressure: 6 mice in the control group administered with PBS, and 7 mice in the plasminogen group. Plasminogen was administered to the mice in the plasminogen group at 2 mg / 0.2 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the control group administered with PBS via tail vein injection for 28 consecutive days. On the 29th day, the mice were sacrificed, and the hearts were taken and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed tissue samples were dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 4 μm thick. The sections were deparaffinized, rehydrated, and then immersed in water, stained with hematoxylin and eosin (H&E staining), fractionated in 1% hydrochloric acid alcohol, blued with ammonia water, dehydrated in an alcohol gradient, and mounted. The sections were then observed under an optical microscope at 200x magnification. As a result, compared with the solvent PBS-treated control group (Figure 4A), the cardiomyocytes of the mice in the plasminogen-treated group (Figure 4B) were denser and more regularly arranged, indicating that plasminogen can significantly improve cardiac damage in diabetic hypertension model mice. Example 5

[0122] Example 5 relates to the effect of plasminogen on reducing renal fibrosis in diabetic hypertension model mice. Thirteen db / db male mice aged 25-26 weeks were taken, and their basal blood pressure was measured after weight measurement the day before administration. They were randomly divided into two groups according to their blood pressure: 6 mice in the control group administered with PBS and 7 mice in the plasminogen group. Plasminogen was administered to the mice in the plasminogen group at 2 mg / 0.2 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the control group administered with PBS via tail vein injection for 28 consecutive days. On the 29th day, the mice were sacrificed, and the kidneys were collected and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. Sirius Red staining can permanently stain collagen. As a special staining method for pathological sections, Sirius Red staining can specifically display collagen tissue. As a result, 28 days after plasminogen administration, the deposition of collagen fibers (marked by arrows) in the kidneys of the plasminogen-administered group (Figure 5B) was significantly less than that of the solvent PBS-administered control group (Figure 5A). This indicates that plasminogen can significantly reduce renal fibrosis in diabetic hypertension model mice. Example 6

[0123] Example 6 relates to the effect of plasminogen on increasing serum SOD levels in angiotensin II-induced hypertensive mouse models. Fourteen Plg+ / + male mice aged 21-22 weeks were taken, and their blood pressure and body weight were measured. The mice were randomly divided into three groups according to their blood pressure and body weight: four mice in the blank control group, five mice each in the PBS-treated control group and the plasminogen-treated group. The blank control group mice were subcutaneously injected with 0.1 ml of saline, and the PBS-treated control group and the plasminogen-treated group mice were subcutaneously injected with angiotensin II at 1 mg / kg / mouse / day for 14 consecutive days for modeling.

[26] Simultaneously with the start of modeling, administration of plasminogen or solvent was started, and plasminogen was administered at 1 mg / 0.1 ml / mouse / day via tail vein injection to the mice in the plasminogen-administered group, and the same amount of PBS solution was administered via tail vein injection to the mice in the PBS-administered control group for 14 consecutive days. No administration was administered to the mice in the blank control group. The day when administration began after modeling was set as day 1, and on the 15th day, the eyeballs were enucleated and blood was collected, and the supernatant was obtained by centrifugation to detect serum superoxide dismutase (SOD) levels. SOD was detected using an SOD detection kit (Nanjing Jiancheng Biotechnology Institute, catalog number A001-1) according to the method described in the instruction manual. SOD is an important enzyme system for the body to eliminate free radicals, and can eliminate superoxide anion (O2-), which is the initiating free radical of oxygen free radicals. Studies have shown that SOD has a protective effect against hypertension, and SOD levels are reduced in hypertensive patients.

[27] . The results showed that the serum of the blank control group had a certain level of SOD, the serum SOD level of the PBS-treated control group was significantly decreased, and the serum SOD level of the plasminogen-treated group was significantly higher than that of the PBS-treated control group, and the difference was statistically significant (* indicates P<0.05) (Figure 6). This indicates that plasminogen can enhance the body's ability to remove free radicals. Example 7

[0124] Example 7 relates to the effect of plasminogen on reducing renal fibrosis in angiotensin II-induced hypertensive mouse models. Fourteen Plg+ / + male mice aged 21-22 weeks were taken, and their blood pressure and body weight were measured. The mice were randomly divided into three groups according to their blood pressure and body weight: four mice in the blank control group, five mice each in the PBS-treated control group and the plasminogen-treated group. The blank control group mice were subcutaneously injected with 0.1 ml of saline, and the PBS-treated control group and the plasminogen-treated group mice were subcutaneously injected with angiotensin II at 1 mg / kg / mouse / day for 14 consecutive days for modeling.

[26] Simultaneously with the start of modeling, administration of plasminogen or solvent was started, and plasminogen was administered at 1 mg / 0.1 ml / mouse / day via tail vein injection to the mice in the plasminogen-treated group, and the same amount of PBS solution was administered via tail vein injection to the mice in the PBS-treated control group for 14 consecutive days. No administration was administered to the mice in the blank control group. The day of modeling and administration was set as day 1, and on the 15th day, the mice were sacrificed, and their kidneys were collected and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed kidney tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. As a result, there was no obvious collagen fiber deposition in the kidneys of mice in the blank control group (Figure 7A), and the deposition of collagen fibers (marked by arrows) in the plasminogen group (Figure 7C) was significantly less than that in the solvent PBS-treated control group (Figure 7B). This indicates that plasminogen can significantly reduce renal fibrosis in angiotensin II-induced hypertension model mice and ameliorate renal lesions caused by hypertension. Example 8

[0125] Example 8 relates to the effect of plasminogen on the reduction of cardiac fibrosis in angiotensin II-induced hypertensive mouse models. 21-22 week old Plg + / + Fourteen male mice were taken, and their blood pressure and body weight were measured. The mice were randomly divided into three groups according to their blood pressure and body weight: four mice in the blank control group, five mice each in the PBS-treated control group and the plasminogen-treated group. The mice in the blank control group were subcutaneously injected with 0.1 ml of saline, and the mice in the PBS-treated control group and the plasminogen-treated group were subcutaneously injected with angiotensin II at 1 mg / kg / mouse / day, and modeled by continuous injection for 14 days.

[26] Simultaneously with the start of modeling, administration of plasminogen or solvent was started. Plasminogen was administered to mice in the plasminogen-treated group at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to mice in the PBS-treated control group via tail vein injection for 14 consecutive days. No administration was administered to mice in the blank control group. The day of modeling and administration was set as day 1, and on the 15th day, the mice were sacrificed, and their hearts were taken and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed cardiac tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. As a result, there was no obvious collagen fiber deposition in the hearts of mice in the blank control group (Figure 8A), and the deposition of collagen fibers (marked by arrows) in the plasminogen group (Figure 8C) was significantly less than that in the solvent PBS-treated control group (Figure 8B). This indicates that plasminogen can significantly reduce cardiac fibrosis in angiotensin II-induced hypertension model mice and improve cardiac lesions caused by hypertension. Example 9

[0126] Example 9 relates to the effect of plasminogen on reducing pulmonary fibrosis in a mouse model of monocrotaline-induced pulmonary arterial hypertension. Twelve 12-week-old C57 male mice were taken, and their weights and blood pressures were measured. The mice were randomly divided into two groups according to their blood pressure: 4 mice in the blank control group and 8 mice in the model group. The mice in the blank control group were administered 100 μl of saline via tail vein injection, and the mice in the model group were administered 60 mg / kg / mouse of monocrotaline via tail vein injection for three consecutive days. The mice were fed a normal diet. [28,29] After 3 days, blood pressure was measured, and the model mice were randomly divided into two groups according to blood pressure: a PBS-treated control group and a plasminogen-treated group, each of which had 4 mice. Plasminogen was administered to the mice in the plasminogen-treated group at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the PBS-treated control group via tail vein injection for 28 consecutive days. No administration was administered to the mice in the blank control group. The day when administration began after modeling was set as day 1, and on the 29th day, the mice were sacrificed, and the lungs were collected and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed lung tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. Monocrotaline is a bipyrrole alkaloid that can be converted by P450 monooxygenase in the liver and then reach the lungs via the blood circulation, where it can cause irreversible damage to pulmonary vascular tissue. Pulmonary vascular endothelial cells are thought to be the target cells of monocrotaline, and damage to endothelial cells plays an important role in the process of pulmonary vascular remodeling. [28,29] . As a result, there was essentially no collagen deposition in the lungs of mice in the blank control group (Figure 9A), and the collagen deposition (marked by arrows) in the lung tissues of mice in the plasminogen group (Figure 9C) was significantly less than that in the solvent PBS-treated control group (Figure 9B). This indicates that plasminogen can significantly reduce lung fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Example 10

[0127] Example 10 relates to the effect of plasminogen on the reduction of cardiac fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Twelve 12-week-old C57 male mice were taken, and their weights and blood pressures were measured. The mice were randomly divided into two groups according to their blood pressure: 4 mice in the blank control group and 8 mice in the model group. The mice in the blank control group were administered 100 μl of saline via tail vein injection, and the mice in the model group were administered 60 mg / kg / mouse of monocrotaline via tail vein injection for three consecutive days. The mice were fed a normal diet. [28,29] After 3 days, blood pressure was measured, and the model mice were randomly divided into two groups according to blood pressure: a PBS-treated control group and a plasminogen-treated group, each of which had 4 mice. Plasminogen was administered to the mice in the plasminogen-treated group at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the PBS-treated control group via tail vein injection for 28 consecutive days. No administration was administered to the mice in the blank control group. The day when administration began after modeling was set as day 1, and on the 29th day, the mice were sacrificed, and the hearts were taken and fixed in 4% paraformaldehyde fixative for 24 hours. The fixed cardiac tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. As a result, there was essentially no collagen deposition in the hearts of mice in the blank control group (Figure 10A), and collagen deposition (marked by arrows) in the hearts of mice in the plasminogen group (Figure 10C) was significantly less than that in the solvent PBS-treated control group (Figure 10B). This indicates that plasminogen can significantly reduce cardiac fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Example 11

[0128] Example 11 relates to the effect of plasminogen on reducing renal fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Twelve 12-week-old C57 male mice were taken, and their weights and blood pressures were measured. The mice were randomly divided into two groups according to their blood pressure: 4 mice in the blank control group and 8 mice in the model group. The mice in the blank control group were administered 100 μl of saline via tail vein injection, and the mice in the model group were administered 60 mg / kg / mouse of monocrotaline via tail vein injection for three consecutive days. The mice were fed a normal diet. [28,29]After 3 days, blood pressure was measured, and the model mice were randomly divided into two groups according to blood pressure: a PBS-treated control group and a plasminogen-treated group, each of which had 4 mice. Plasminogen was administered to the mice in the plasminogen-treated group at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the PBS-treated control group via tail vein injection for 28 consecutive days. No administration was administered to the mice in the blank control group. The day when administration began after modeling was set as day 1, and on the 29th day, the mice were sacrificed, and the kidneys were collected and fixed in 4% paraformaldehyde solution for 24 hours. The fixed kidney tissue was dehydrated in an alcohol gradient, permeabilized with xylene, and embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. As a result, there was essentially no collagen deposition in the kidneys of mice in the blank control group (Figure 11A), and collagen deposition (marked by arrows) in the kidneys of mice in the plasminogen group (Figure 11C) was significantly less than that in the solvent PBS-treated control group (Figure 11B). This indicates that plasminogen can significantly reduce kidney fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Example 12

[0129] Example 12 relates to the effect of plasminogen on reducing hepatic fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Twelve 12-week-old C57 male mice were taken, and their weights and blood pressures were measured. The mice were randomly divided into two groups according to their blood pressure: 4 mice in the blank control group and 8 mice in the model group. The mice in the blank control group were administered 100 μl of saline via tail vein injection, and the mice in the model group were administered 60 mg / kg / mouse of monocrotaline via tail vein injection for three consecutive days. The mice were fed a normal diet. [28,29] After 3 days, blood pressure was measured, and the model mice were randomly divided into two groups according to blood pressure: a PBS-treated control group and a plasminogen-treated group, each of which had 4 mice. Plasminogen was administered to the mice in the plasminogen-treated group at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the mice in the PBS-treated control group via tail vein injection for 28 consecutive days. No administration was administered to the mice in the blank control group. The day when administration began after modeling was set as day 1, and on the 29th day, the mice were sacrificed, and their livers were collected and fixed in 4% paraformaldehyde fixative for 24 hours. The liver tissue after fixation was dehydrated in an alcohol gradient, permeabilized with xylene, and then embedded in paraffin. The tissue sections were 3 μm thick, and the sections were deparaffinized, rehydrated, and washed once with water. After staining with 0.1% Sirius Red saturated with picric acid for 30 minutes, the sections were rinsed with running water for 2 minutes, stained with hematoxylin for 1 minute, rinsed with running water, differentiated with 1% hydrochloric acid alcohol, bluing with ammonia water, rinsed with running water, dried, and then mounted in neutral rubber. The sections were then observed under an optical microscope at 200x magnification. As a result, there was essentially no collagen deposition in the livers of mice in the blank control group (Figure 12A), and collagen deposition (marked by arrows) in the livers of mice in the plasminogen group (Figure 12C) was significantly less than that in the solvent PBS-treated control group (Figure 12B). This indicates that plasminogen can significantly reduce liver fibrosis in monocrotaline-induced pulmonary arterial hypertension model mice. Example 13

[0130] Example 13 relates to the fact that plasminogen promotes an increase in blood pressure in mice with ischemic renal atrophy. Eighteen 6-7 week old C57 male mice were taken and randomly divided into two groups, 4 in the blank control group and 14 in the model group. The blank control group mice were not treated in any way. The model group mice were anesthetized by intraperitoneal injection of 3% sodium pentobarbital (50mg / kg), the skin, fascia, and muscle layers were surgically incised at the midline of the abdomen, the intestines, pancreas and other organ tissues were opened, the surgical field was exposed, the aorta and main vein of the renal pelvis of the left kidney were bluntly separated, the separated blood vessels were ligated with No. 5 silk thread, and after confirming that the ligation was completed, the intestines, pancreas and other organ tissues were returned to the corresponding physiological positions, the muscle layers were surgically sutured continuously, and the skin was sutured with interrupted sutures. After suturing, the wound was disinfected with medical iodophor, the animals were placed on a 37℃ heating pad and observed to revive, and no water was given until the animals were fully revived. Antibiotics (5000U / mouse) were injected intramuscularly and analgesics (2mg / kg) were injected subcutaneously for 3 consecutive days. 14 days after surgical ligation, the mice in the model group were anesthetized by intraperitoneal injection of 3% sodium pentobarbital, the abdomen was opened, the ligature of the left renal vessels was loosened, the abdominal cavity was quickly sutured, the wound was disinfected with medical iodophor, the animals were placed on a 37°C heating pad, observed and waited to revive, and water was withheld until the animals were fully revived. Antibiotics (5000U / mouse) were injected intramuscularly and analgesics (2mg / kg) were injected subcutaneously for 3 consecutive days.

[30] After the sutures were removed, the weights of all mice were measured, and the mice in the model group were randomly divided into two groups, a plasminogen-administered group and a PBS control group, with seven mice in each group, and administration was started. The day administration began was designated as day 1, and plasminogen was administered to the mice in the plasminogen-administered group at 1 mg / 0.1 ml / mouse / day via tail vein injection, while the mice in the PBS-administered control group were administered the same amount of PBS solution via tail vein injection for 14 consecutive days. On the 15th day, the blood pressure (systolic and mean pressure) of the mice was measured using a non-invasive blood pressure monitor (MRBP-M01, IITC Life science). As a result, the systolic and mean pressures of the plasminogen-administered group and the blank control group were significantly higher than that of the PBS control group, and the difference between the plasminogen-administered group and the PBS control group was statistically significant (* indicates P<0.05) (FIG. 13). This indicates that plasminogen can promote the recovery of hypotension caused by renal atrophy to normal levels. Example 14

[0131] Example 14 relates to the effect of plasminogen in lowering blood pressure in angiotensin II-induced hypertensive mouse models. Twenty-one C57 male mice aged 8-9 weeks were randomly divided into three groups: blank control group, vehicle group, and treatment group, with seven mice in each group. The mice in the blank control group were not treated with any drugs. The mice in the treatment group and vehicle group were subcutaneously injected with 0.25 mg / ml angiotensin II solution at 1 mg / kg / mouse, and modeled twice a day with an interval of 8 hours for six consecutive days.

[31] Two hours after the first injection of angiotensin II, administration to the treatment group and the vehicle group began, which was designated as day 1. Plasminogen was administered to the treatment group mice at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the vehicle group mice via tail vein injection for 5 consecutive days, and the blank control group was not administered. On the 6th day, the blood pressure of all mice was measured, and measurements were taken five consecutive times per mouse, with the systolic pressure and mean pressure recorded for each measurement. The systolic pressure and mean blood pressure are the average values ​​of the systolic pressure and mean pressure data obtained from the five measurements, respectively. The blood pressure of the mice was measured using a non-invasive blood pressure monitor (MRBP-M01, IITC Life science). As a result, the mean and systolic pressures of the mice in the vehicle group increased significantly, and the mean and systolic pressures of the mice in the administration group were significantly lower than those of the mice in the vehicle group, and the difference was statistically significant (* indicates P<0.05, ** indicates P<0.01) (Figure 14). This indicates that plasminogen can lower the blood pressure of hypertension model mice. Example 15

[0132] Example 15 relates to the effect that plasminogen increases the level of angiotensin-converting enzyme 2 in diabetic hypertension model mice. Twelve db / db male mice aged 24-25 weeks were taken, and their basal blood pressure was measured after weight measurement on the day before administration. They were randomly divided into two groups, a vehicle group and a treatment group, with six mice in each group, according to their blood pressure. Plasminogen was administered to the treatment group mice at 2 mg / 0.2 ml / mouse / day via tail vein injection, and the same amount of PBS solution was administered to the vehicle group mice via tail vein injection for 28 consecutive days. On the 29th day, the eyes were removed and blood was collected, and the supernatant was obtained by centrifugation. Serum ACE2 levels were detected according to the instructions of the angiotensin-converting enzyme 2 (ACE2) detection kit (manufacturer: Wuhan Huamei Biotechnology Co., Ltd., catalog number: CSB-E17204m). Angiotensin-converting enzyme 2 (ACE2) is an important negative regulator of the renin-angiotensin system and the main pathway for the degradation of angiotensin II (AngII) in the body. Under the action of ACE2, AngII is converted to Angl-7. ACE2 can also catalyze the degradation of AngI to Ang(1-9), the latter of which is converted to Angl-7 by ACE. The affinity of ACE2 for AngII is 400-fold higher than that of AngI, and the main function of ACE2 is to catalyze the conversion of AngII to Ang(1-7). The physiological roles of ACE2 are associated with hypertension, cardiac function, heart function, and diabetes, and it also serves as a receptor for severe acute respiratory syndrome coronavirus.

[32] . As a result, the serum ACE2 levels of the mice in the treatment group were significantly higher than those in the vehicle group, and the statistical difference was close to significance (P = 0.057) (Figure 15). This indicates that plasminogen can promote an increase in serum ACE2 levels in diabetic hypertension model mice. Example 16

[0133] Example 16 relates to the effect of plasminogen on reducing serum ACE2 levels in angiotensin II-induced hypertensive mouse models. Twenty-one C57 male mice aged 8 to 9 weeks were taken and randomly divided into three groups: a blank control group, a solvent group, and a treatment group, with seven mice in each group. After grouping was completed, mice in the treatment group and solvent group were subcutaneously injected with 0.25 mg / ml angiotensin II solution at 1 mg / kg / mouse, and modeled twice a day with an interval of 8 hours for 7 consecutive days. Preparation of angiotensin II solution: First, angiotensin II powder (catalog number: A9292-10mg, manufacturer: Beijing Solarbio Science & Technology Co., Ltd.) was dissolved in 1 ml of deionized water to prepare a 10 mg / ml solution, which was then dispensed and packaged to avoid repeated freezing and thawing, and when used, it was diluted 40 times to prepare 0.25 mg / ml and used, and the original solution was stored at -20 °C. Two hours after the first injection, administration began for the treatment group and the vehicle group, which was designated as day 1. Plasminogen was administered to the treatment group mice at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the same amount of vehicle was administered to the vehicle group mice via tail vein injection for 7 consecutive days, and no vehicle was administered to the blank control group. On the 8th day, the eyes were removed and blood was collected, and the supernatant was obtained by centrifugation. Serum ACE2 levels were detected according to the instructions for the angiotensin-converting enzyme 2 (ACE2) detection kit (manufacturer: Shanghai Xi Mei Chemical Co., Ltd., catalog number: CSB-E17204m). As a result, there was a certain level of ACE2 in the blood of the blank control group mice, the ACE2 level in the blood of the vehicle group mice was significantly higher than that of the blank control group mice, and the ACE2 level in the blood of the treatment group mice was significantly lower than that of the vehicle group mice, and the difference was statistically highly significant (** represents P<0.01) (Figure 16). This indicates that plasminogen can promote the reduction of serum ACE2 levels in angiotensin II-induced hypertension model mice. Example 17

[0134] Example 17 relates to the effect of plasminogen on the reduction of serum ACE levels in angiotensin II-induced hypertensive mouse models. Twenty-one C57 male mice aged 8 to 9 weeks were taken and randomly divided into three groups: a blank control group, a solvent group, and a treatment group, with seven mice in each group. After grouping was completed, mice in the treatment group and solvent group were subcutaneously injected with 0.25 mg / ml angiotensin II solution at 1 mg / kg / mouse, and modeled twice a day with an interval of 8 hours for 7 consecutive days. Preparation of angiotensin II solution: First, angiotensin II powder (catalog number: A9292-10mg, manufacturer: Beijing Solarbio Science & Technology Co., Ltd.) was dissolved in 1 ml of deionized water to prepare a 10 mg / ml solution, which was then dispensed and packaged to avoid repeated freezing and thawing, and when used, it was diluted 40 times to prepare 0.25 mg / ml and used, and the original solution was stored at -20 °C. Two hours after the first injection, the administration of plasminogen to the treatment group and the vehicle group was started, which was designated as the first day. The treatment group mice were administered plasminogen at 1 mg / 0.1 ml / mouse / day via tail vein injection, and the vehicle group mice were administered the same amount of vehicle via tail vein injection for 7 consecutive days, and the blank control group mice were not administered the same amount of vehicle. On the 8th day, the eyes were enucleated and blood was collected, and the supernatant was obtained by centrifugation. Serum ACE levels were detected according to the instructions of the angiotensin-converting enzyme (ACE) detection kit (manufacturer: Wuhan Huamei Biotechnology Co., Ltd., catalog number: CSB-E04492m). Angiotensin-converting enzyme (ACE) is a key enzyme of the renin-angiotensin system and plays a key role in the production of AngII.

[32] . The results showed that the blank control mice had a certain level of ACE in their blood, the ACE levels in the vehicle mice were significantly higher than those in the blank control mice, and the ACE levels in the treatment mice were significantly lower than those in the vehicle mice, and the statistical differences were close to significance (P=0.051) (Figure 17). This indicates that plasminogen can promote the reduction of serum ACE levels in AngII-induced hypertension model mice. Example 18

[0135] Example 18 concerns the therapeutic effect of plasminogen on clinical volunteers. The following are data from clinical volunteers, and all patients signed an informed consent form to voluntarily take the drug, and approval was obtained from the hospital ethics committee. The plasminogen used below was diluted with saline to a concentration of 5 or 10 mg / ml. For inhalation administration, the plasminogen solution was atomized (aerosolized) with a nebulizer before use.

[0136] Case 1 The patient was a 72-year-old woman with a history of hypertension for over 30 years, with a systolic pressure of 160mmHg, occasionally 180mmHg, and after taking antihypertensive drugs, her blood pressure was controlled at about 130 / 80mmHg. The patient received intravenous injections of human plasminogen once a day, with a starting dose of 50mg / dose, which was gradually increased to 135mg / dose. The patient's systolic pressure dropped to 141mmHg on the sixth day after administration, and by the eleventh day, her blood pressure fluctuated and became unstable (alternating between normal and abnormal), and after the twelfth day, her blood pressure dropped and was normal and stable within a week. The patient was not taking antihypertensive drugs while receiving the above intravenous plasminogen therapy. The patient's blood pressure during the administration period is shown in Figure 18. This indicates that plasminogen can lower the blood pressure of hypertensive patients and bring it closer to normal levels.

[0137] Case 2 The patient was a 79-year-old woman with a history of coronary heart disease for more than 20 years who developed a cerebral infarction in 2014. She had a 23-year history of diabetes and had been receiving long-term insulin injections. She had been diagnosed with hypertension for 5 years, and after taking antihypertensive medication, her blood pressure was 130-150 / 50-60 mmHg in the morning and about 150 / 60 mmHg in the afternoon. Human plasminogen was administered to the patient by intravenous injection at 100 mg / dose once daily. The patient's blood pressure was 135 / 54 mmHg on the 13th day after administration, and thereafter stabilized at a normal level without the need for antihypertensive drugs. The patient's blood pressure during the administration period is shown in Figure 19.

[0138] Case 3 The patient was a 76-year-old woman with a 20-year history of diabetes and 10 years of hypertension, with a maximum blood pressure of 168 / 70 mmHg. After oral administration of nifedipine sustained-release tablets, the blood pressure was controlled at approximately 114 / 55 mmHg, and the diastolic pressure was lower than normal. Human plasminogen was administered to the patient by intravenous injection once or twice a day at a dose of 35 to 75 mg per day. After administration, the diastolic pressure reached normal from less than 60 mmHg before, and blood pressure during treatment was normal and stable. After treatment, the antihypertensive drugs were reduced by half, and blood pressure was basically controlled at 130-140 / 64-76 mmHg. The patient's blood pressure during the administration period is shown in Figure 20. Plasminogen helps to normalize blood pressure in hypertensive patients and allows for a reduction in the dosage of antihypertensive drugs.

[0139] Case 4 The patient was a 57-year-old man who was admitted for reexamination and found to have thickened abdominal aorta and diagnosed with aortic dissection. The hospital recommended surgery. There was a family history of heart disease and a history of hypertension for more than 10 years. The patient was allergic to contrast media and had eczema and urticaria. His blood pressure was high in the morning and evening, with the highest systolic pressure reaching 200mmHg, and the blood pressure difference was large, sometimes reaching 80mmHg or more. He had poor sleep, was slow to fall asleep, and woke up 3-4 times in the middle of the night, which affected his sleep. Human plasminogen was administered to patients by intravenous injection once or twice daily at a dose of 50 to 150 mg / day. After the fifth day of administration, morning and evening blood pressure began to decrease, and the difference in blood pressure became smaller. The patient reported that this was the first improvement, as her blood pressure had never dropped below 140 / 75 mmHg even when taking antihypertensive drugs before. From the sixth day of administration, morning and evening blood pressure was maintained at approximately 136 / 73 mmHg. From the seventh day of administration, the blood pressure in the morning and evening was stable, and was about 130 / 70 mmHg. The patient's blood pressure during the administration period is shown in Figure 21. Also, on the fifth day of taking the drug, the patient's sleep improved significantly and he no longer woke up during the night. The symptoms of eczema and hives also improved significantly. Since then, the patient's condition has continued to improve.

[0140] Case 5 The patient was 78 years old and was diagnosed with severe novel coronavirus pneumonia. During the hospitalization treatment period, the patient was found to have an elevated blood pressure of 150 / 78 mmHg. Since he had no history of hypertension, he did not seek medical advice. Human plasminogen was administered to the patient by aerosol inhalation at 10 mg twice a day. The blood pressure returned to normal after one day. The patient's blood pressure during the treatment period is shown in Tables 1 and 2. This indicates that plasminogen can promote the recovery of hypertension to normal in severe patients with novel coronavirus pneumonia. Table 1. Blood pressure measurement results on the first day of medication in patients with severe COVID-19 pneumonia JPEG2025000825000001.jpg17154Table 2 Blood pressure measurement results on the second day of medication in patients with severe COVID-19 pneumonia JPEG2025000825000002.jpg17154

[0141] Case 6 The patient was diagnosed with severe novel coronavirus pneumonia and, in addition to relevant clinical symptoms, had a blood pressure of 139 / 94 mmHg and a higher than normal diastolic pressure. Plasminogen was administered to the patient by aerosol inhalation twice a day, 10 mg each time. The diastolic pressure returned to normal after one treatment. The patient's blood pressure during the treatment period is shown in Table 3. Plasminogen can promote the recovery of hypertension to normal in severe patients with novel coronavirus pneumonia. Table 3. Blood pressure measurement results for patients with severe COVID-19 pneumonia while taking medication JPEG2025000825000003.jpg17154

[0142] Case 7 The patient was a 67-year-old woman, bedridden, unable to speak due to a tracheotomy, with no history of diabetes, heart disease, hypertension, or allergies. She had been suffering from Parkinson's disease for 6 years, unable to walk for 4 years, bedridden for 3 years, and had a catheter in place for 1.5 years. The patient was unable to turn over in bed on her own, was able to move her limbs on her own, and was continuously inhaling low-flow oxygen every day. Her blood pressure was 80 / 45 mmHg. She was diagnosed with hypotension and Parkinson's disease. The patient was given plasminogen by intravenous injection once a day at a dose of 50-250 mg / day, with an initial dose of 50 mg / day and gradually increased. The patient was given plasminogen for 7 consecutive days, continued on the 9th, 11th, and 13th days, and discontinued on the 8th, 10th, and 12th days for observation. Therapeutic effect: Blood pressure showed a tendency to rise after administration, and normal blood pressure appeared for the first time on the third day of administration. Blood pressure remained normal from the ninth day of administration onwards, and after discontinuation of the drug, blood pressure remained at 95 / 70 mmHg. The results of blood pressure measurements of the patients during the treatment period are shown in Figure 22. This indicates that plasminogen can promote blood pressure recovery in hypotensive patients.

[0143] Case 8 The patient was a 50-year-old woman with a long history of hypotension, with a low blood pressure of 80 / 60 mmHg on weekdays and occasional morning dizziness. She was diagnosed with hypotension. Treatment: intravenous injection, once a day, dose 100 mg. Treatment results: After administration, the patient's blood pressure returned to normal the day after administration and reached about 110 / 70 mmHg one week later. The results of measuring the patient's blood pressure during the treatment period are shown in Figure 23. This shows that plasminogen can promote blood pressure recovery in patients with low blood pressure. References: [1] Alexander CM and Werb, Z. (1991). Extracellular matrix degradation. In Cell Biology of Extracellular Matrix, Hay ED, ed. (New York: Plenum Press), pp. 255-302. [2] Werb, Z., Mainardi, C.L., Vater, C.A., and Harris, E.D., Jr. (1977). Endogenous activiation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator. N. Engl. J. Med. 296, 1017-1023. [3] He, C.S., Wilhelm, S.M., Pentland, A.P., Marmer, B.L., Grant, G.A., Eisen, A.Z., and Goldberg, G.I. (1989). Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc. Natl. Acad. Sci. U. S. A 86, 2632-2636. [4] Stoppelli, M.P., Corti, A., Soffientini, A., Cassani, G., Blasi, F., and Assoian, R.K. (1985). Differentiation-enhanced binding of the amino-terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc. Natl. Acad. Sci. U. S. A 82, 4939-4943. [5]Vassalli, J.D., Baccino, D., and Belin, D. (1985). A cellular binding site for the Mr 55, 000 form of the human plasminogen activator, urokinase. J. Cell Biol. 100, 86-92. [6] Wiman, B. and Wallen, P. (1975). Structural relationship between “glutamic acid” and “lysine” forms of human plasminogen and their interaction with the NH2-terminal activation peptide as studied by affinity chromatography. Eur. J. Biochem. 50, 489-494. [7] Saksela, O. and Rifkin, D.B. (1988). Cell-associated plasminogen activation: regulation and physiological functions. Annu. Rev. Cell Biol. 4, 93-126. [8] Raum, D., Marcus, D., Alper, C.A., Levey, R., Taylor, P.D., and Starzl, T.E. (1980). Synthesis of human plasminogen by the liver. Science 208, 1036-1037. [9] Wallen P (1980). Biochemistry of plasminogen. In Fibrinolysis, Kline DL and Reddy KKN, eds. (Florida: CRC)

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Sequence Listing Sequence 1: Array 2: EPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHA HGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDNPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTSQVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKCCQSWSSMTPHRHQKTPE NYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLI SPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN Array 3: Array 4: MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSKEQQCVIMAENRKSSIIIRMRDVLFEKKVYLSECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGKISKTMS GLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTSQVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKCCQSWSSMT PHRHQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGMHFC GGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN Array 5: Array 6: KVYLSECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQ CLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTSQVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKK CSGTEASVVAPPPVVLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPS SYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN Array 7: Array 8: EPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKNGI TCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFG MHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN Array 9: Array 10: VRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEK SPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN Array 11: gccccttcatttgattgtgggaagcctcaagtggagccgaagaaatgtcctggaagggttgtaggggggtgtgtggcccacccacattcctggccctggcaagtcagtcttagaacaaggtttggaatgcacttctgtggaggcaccttgatatccccagagtgggtgttgactgctgccccactgct tggagaagtccccaaggccttcatcctacaaggtcatcctgggtgcacaccaagaagtgaatctcgaaccgcatgttcaggaaataagaagtgtctaggctgttcttggagcccacacgaaaagattgccttgctaaagctaagcagtcctgccgtcatcactgacaaagtaatcccagcttgtctg ccatccccaaattatgtggtcgctgaccggaccgaatgtttcatcactgggctgggagaaacccaaggtacttttggagctggccttctcaaggaagcccagctccctgtgattgagaataaagtgtgcaatcgctatgagtttctgaatggaagagtccaatccaccgaactctgtgctgggcatt tggccggaggcactgacagttgccagggtgacagtggaggtcctctggtttgcttcgagaaggacaaatacatttacaaggatcacttcttggggtcttggctgtgcacgccccataagcctggtgtctatgttcgtgtttcaaggtttgttacttggattgagggagtgatgagaaataattaa array12: APSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRSPYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGGLGCARPNKPGVYVRVSRFVTWIEGVMRNN array13: gttgtaggggggtgtgtggcccacccacattcctggccctggcaagtcagtcttagaacaaggtttggaatgcacttctgtggaggcaccttgatatccccagagtgggtgttgactgctgccccactgcttggagaagtccccaaggccttcatcctacaaggtcatcctg ggtgcacaccaagaagtgaatctcgaaccgcatgttcaggaaatagaagtgtctaggctgttcttggagcccacacgaaaagattgccttgctaaagctaagcagtcctgccgtcatcactgacaaagtaatcccagcttgtctgccatccccaaattatgtggtcgct gaccggaccgaatgtttcatcactgggctggggagaaacccaaggtacttttggagctggccttctcaaggaagcccagctccctgtgattgagaataaagtgtgcaatcgctatgagtttctgaatggaagagtccaatccaccgaactctgtgctggggcatttggccgga ggcactgacagttgccagggtgacagtggaggtcctctggtttgcttcgagaaggacaaatacatttacaaggatcacttcttggggtcttggctgtgcacgccccaataagcctggtgtctatgttcgtgtttcaaggtttgttacttggattgagggagtgatgaga array14: VVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMR

Claims

[Claim 1] 1. A pharmaceutical composition for the bidirectional treatment of blood pressure abnormalities comprising an effective amount of one or more compounds selected from components of the plasminogen activation pathway, compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, compounds capable of upregulating the expression of plasminogen or plasminogen activators, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors, for administration to a subject suffering from abnormal blood pressure, wherein the abnormal blood pressure is hypertension or hypotension, and the compound normalizes, brings the blood pressure close to normal, or returns it to normal in a subject suffering from hypertension or hypotension. Preferably, the component of the plasminogen activation pathway is selected from plasminogen, recombinant human plasminogen, Lys-plasminogen, Glu-plasminogen, plasmin, plasminogen and plasmin variants and analogs containing one or more kringle domains and protease domains of plasminogen and plasmin, mini-plasminogen, mini-plasmin, micro-plasminogen, micro-plasmin, delta-plasminogen, delta-plasmin, plasminogen activators, tPA, and uPA; More preferably, the fibrinolysis inhibitor antagonist is an antagonist of PAI-1, complement C1 inhibitor, α2-antiplasmin or α2-macroglobulin, e.g. an antibody. The pharmaceutical composition.

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