Method for improving plateau hypertension by using GsMTx4 compound

Abstract

The invention discloses a method for improving plateau hypertension by using a GsMTx4 compound, which is characterized in that the GsMTx4 compound is used as a Piezo1 inhibitor, and endothelial cell injury of a cardiovascular system is regulated through mitochondrial autophagy mediated by BNIP3, so that the plateau hypertension is reduced. A new treatment target is provided for damage of the plateau hypertension endothelial cells, and a new technology is provided for treatment of the plateau hypertension.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular, relates to a method for improving plateau hypertension by utilizing a GsMTx4 compound. Background Art

[0002] Plateau hypertension refers to the increase in blood pressure that occurs when people who live in plains move to plateaus (areas above 3000m above sea level), with diastolic blood pressure at 90mmHg and systolic blood pressure above 140mmHg. In plateau environments, due to hypoxia and low pressure, the incidence of hypertension is higher than in plain areas. A retrospective study involving 16,913 subjects reported a significant correlation between altitude and the prevalence of hypertension. When the altitude exceeded 3000m, the prevalence of hypertension increased by 2% for every increase of about 100m in altitude. Studies have shown that altitude is positively correlated with blood pressure, and blood pressure increases by 17.0 / 9.5mm Hg for every increase of 1km in altitude. More than 100 million people climb mountainous areas worldwide every year, and literature reports that young men who were first exposed to 4500m areas still had a high incidence of hypertension for half a year. The above data suggest that plateau hypertension has a high prevalence, and long-term plateau hypertension can cause related damage to target organs such as the heart, brain, kidneys, and blood vessels, seriously threatening human health. Therefore, it is of great significance to study the mechanism of plateau hypertension and use the mechanism for treatment.

[0003] Endothelial cells play an important role in maintaining blood pressure and vascular integrity, and endothelial dysfunction is an important mechanism for the occurrence and development of hypertension and its target organ damage. Endothelial cells are distributed throughout the inner wall of blood vessels and are the first line of defense for the cardiovascular system to fight against the balance of internal and external factors. Endothelial cell dysfunction, such as changes in autophagy and apoptosis, can increase vascular damage. Dysfunction of vascular endothelial cells in hypertensive patients, such as the secretion homeostasis of nitric oxide and endothelin, causes vasoconstriction, increases circulatory resistance, and ultimately leads to the occurrence of hypertension. Increased blood pressure promotes apoptosis of microvascular endothelial cells, reduces parallel blood pathways, enhances peripheral circulatory resistance, and ultimately leads to hypertension. Therefore, vascular endothelial cell damage plays an important role in the development of hypertension.

[0004] Piezo1 is a mechanosensitive cation channel. When mechanically stimulated, Piezo1 helps cations enter cells and converts mechanical signals into chemical signals, thereby inducing cell excitation and signal transduction. As a non-selective cation channel, Piezo1 can mainly regulate Ca 2 +(Ca 2+ influx), while Ca 2+As a second messenger, the downstream signaling pathway plays a key role in changes in endothelial cell injury, blood pressure regulation, vascular tension, etc. GsMTx4, as an inhibitor of the Piezo1 channel, binds to the cell membrane, enters the lipid bilayer by inserting its hydrophobic domain, directly acts on the membrane of the backbone protein, blocks the mechanical force, and transmits it by changing the tension of the membrane, thereby achieving the blockade of the Piezo1 ion channel.

[0005] Piezo1 plays an important role in the occurrence and development of cardiovascular diseases. The vasodilatory effect of Piezo1 is based on the synthesis of NO by endothelial cells. Endothelial cell Piezo1 can also specifically regulate the contraction of certain blood vessels. Piezo1 is highly expressed in endothelial cells, and its upregulation can cause a series of changes in endothelial cells. Piezo1 can cause pathological changes in endothelial cells. It acts upstream of TRPV4, causing shear stress changes and then pathological changes in endothelial cells. Studies have shown that Piezo1 can also cause mitochondrial damage in vascular endothelial cells.

[0006] However, the regulatory role of Piezo1 and endothelial cells in hypertension, especially high-altitude hypertension, has not yet been elucidated. Summary of the invention

[0007] Based on a large number of past studies, the present invention proposes the following hypothesis: Under high-altitude hypertension, Piezo1 in endothelial cells is stimulated by pressure, and the channel opens, causing Ca 2+ Excessive calcium influx may cause FOXO3 upregulation, thereby activating BNIP3-mediated mitochondrial autophagy. 2+ Influx promotes mitochondrial dysfunction, ultimately causing endothelial cell damage. The present invention first clarifies the molecular mechanism of Piezo1 regulating endothelial cell damage through BNIP3-mediated mitochondrial autophagy, providing a new therapeutic target for high-altitude hypertension.

[0008] Based on the above findings, the technical solution proposed by the present invention to solve the above technical problems is as follows:

[0009] A first aspect of the present invention provides a use of a Piezo1 inhibitor in the preparation of a drug for treating hypertension.

[0010] Preferably, the Piezo1 inhibitor is a substance that inhibits Piezol activity or a substance that reduces Piezol levels;

[0011] More preferably, the substance that inhibits Piezol activity is selected from GsMTx4, thapsigargin or cytochalasin D;

[0012] More preferably, the substance that inhibits Piezol activity is a GsMTx4 polypeptide, whose sequence is as follows: Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Lys-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe-NH2.

[0013] The second aspect of the present invention provides a use of a Piezo1 inhibitor in the preparation of a drug for treating high-altitude hypertension.

[0014] Preferably, the Piezo1 inhibitor is a substance that inhibits Piezol activity or a substance that reduces Piezol levels;

[0015] More preferably, the substance that inhibits Piezol activity is selected from GsMTx4, thapsigargin or cytochalasin D;

[0016] More preferably, the substance that inhibits Piezol activity is a GsMTx4 polypeptide, whose sequence is as follows: Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Lys-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe-NH2.

[0017] The third aspect of the present invention provides a use of a Piezo1 inhibitor in the preparation of a drug for treating vascular endothelial injury caused by high altitude hypertension.

[0018] Preferably, the Piezol inhibitor is a substance that inhibits Piezol activity or a substance that reduces Piezol levels.

[0019] More preferably, the substance that inhibits Piezol activity is selected from GsMTx4, thapsigargin or cytochalasin D.

[0020] A fourth aspect of the present invention provides a use of a BNIP3 inhibitor in the preparation of a drug for treating high-altitude hypertension.

[0021] The fifth aspect of the present invention provides a use of a BNIP3 inhibitor in the preparation of a drug for treating vascular endothelial injury caused by high-altitude hypertension.

[0022] In the present application, the term "treat" refers to alleviating, relieving or improving the symptoms of a disease or condition, improving symptoms caused by potential metabolism, inhibiting a disease or symptom, such as preventing the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating the condition caused by a disease or condition, or preventing the symptoms of a disease or condition.

[0023] In the present application, the "GsMTx4" is a spider venom peptide that selectively inhibits cation-permeable mechanosensitive channels (MSCs) belonging to the Piezo and TRP channel families. GsMTx4 can also block cation-selective stretch-activated channels (SACs) and attenuate lysophosphatidylcholine (LPC)-induced astrocyte toxicity and microglial reactivity. GsMTx4 is an important pharmacological tool that can be used to identify the role of excitatory MSCs in normal physiology and pathology. Its sequence is

[0024] Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Lys-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe-NH2.

[0025] After adopting the above technical scheme, the present invention has the following beneficial effects compared with the prior art.

[0026] The present invention uses GsMTx4 as a Piezo1 inhibitor. GsMTx4 regulates endothelial cell damage through BNIP3-mediated mitochondrial autophagy, thereby reducing the mechanism of high-altitude hypertension, providing a new therapeutic target for endothelial cell damage in high-altitude hypertension and a new technology for the treatment of high-altitude hypertension.

[0027] The specific implementation modes of the present invention are further described in detail below in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings are part of this application and are used to provide a further understanding of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention, but do not constitute an improper limitation of the present invention. Obviously, the drawings described below are only some embodiments. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work. In the drawings:

[0029] Figure 1 It is a bar graph of mouse blood pressure;

[0030] Figure 2 is a bar graph of mouse heart rate;

[0031] Figure 3 is a bar graph of mouse weight;

[0032] Figure 4 This is the bar graph of mouse ET-1 and NO;

[0033] Figure 5 for the differences between Piezo1 and LC3 in mouse aortic endothelium;

[0034] Figure 6 The changes of Piezo1 and mitochondrial autophagy in HAEC (human aortic endothelial cells) under plateau conditions [a. Western blot detection of the expression of Piezo1, BNIP3, LC3Ⅱ / LC3Ⅰ in each group, b. relative expression of Piezo1, c. relative expression of BNIP3, d. relative expression of LC3Ⅱ / LC3Ⅰ];

[0035] Figure 7 Changes of mitochondrial autophagy in HAEC [a. Western blot detection of BNIP3, LC3Ⅱ / LC3Ⅰ, and Tom20 expression in each group, b. relative expression of BNIP3, c. relative expression of LC3Ⅱ / LC3Ⅰ, d. relative expression of Tom20];

[0036] Figure 8 is the intracytoplasmic Ca 2+ concentration map;

[0037] Fig. 9 Mitochondrial membrane potential in HAEC [a. Confocal microscope shows the fluorescence intensity of mitochondrial membrane potential, b. Flow cytometry shows the mitochondrial membrane potential];

[0038] Fig.10 The mitochondrial ROS content increased;

[0039] Fig.11 for the changes of NO and ET-1 in HAEC;

[0040] Fig.12 Changes in HAEC proliferation and migration numbers [a. Transwell migration assay, b. CCK8 assay to detect cell proliferation activity]

[0041] Fig.13 The effect of Piezo1 on mitochondrial autophagy;

[0042] Fig.14 for the effect of Piezo1 on Ca2+;

[0043] Fig.15 The effect of Piezo1 on mitochondrial function;

[0044] Fig.16 The effect of Piezo1 on endothelial cells.

[0045] Fig.17 Effects of knocking down BNIP3 on mitophagy

[0046] Fig.18 Effects of knocking down BNIP3 on mitochondrial function

[0047] Fig.19 Effects of knocking down BNIP3 on endothelial cell function

[0048] It should be noted that these drawings and textual descriptions are not intended to limit the conceptual scope of the present invention in any way, but are intended to illustrate the concept of the present invention for those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0049] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. The following embodiments are used to illustrate the present invention but are not used to limit the scope of the present invention.

[0050] 1. In vivo experiments

[0051] 1.1 Experimental procedures

[0052] a. Construction of high altitude hypertension mouse model

[0053] Wild-type (WT) C57 mice aged 8-12 weeks were randomly divided into two groups: normoxic group: mice were raised under normoxia and normal pressure; high-altitude hypertension group: mice were raised in a hypobaric oxygen chamber (simulating an altitude of 6000 m).

[0054] b. Validation of the high altitude hypertension model

[0055] The blood pressure (tail cuff method), body weight and heart rate of the mice were monitored on days 3 and 7.

[0056] c. Use the Piezo1 inhibitor GsMTx4 (MCE, HY-P1410) to study the effect of Piezo1 inhibitor on the blood pressure of mice with high-altitude hypertension.

[0057] C57 mice were injected intraperitoneally with GsMTx4 (1 mg / kg, 0.5), and placed in a hypobaric oxygen chamber (simulating an altitude of 6000 m). The blood pressure (tail cuff method), body weight, and heart rate of the mice were monitored on the 3rd and 7th days.

[0058] d. Detection of Piezo1

[0059] The thoracic aorta tissues of mice were taken to prepare sections, and the differences of Piezo1 in the aortic endothelium were detected by fluorescent staining.

[0060] f. Endothelial cell function test

[0061] The changes of NO and ET-1 were detected in mouse serum.

[0062] 1.2 Experimental Results

[0063] a. Figure 1 It shows that after 3 and 7 days of feeding mice in the hypobaric oxygen chamber (simulating an altitude of 6000m), the blood pressure of mice increased compared with the control group, and the blood pressure of mice fed for 7 days increased significantly (P<0.05). This shows that the high-altitude hypertension mouse model was successfully constructed. Under the conditions of the hypobaric oxygen chamber, mice were intraperitoneally injected with different doses of GsMTx4 (0.5mg / kg and 1mg / kg), and it was found that the blood pressure of mice decreased, and the blood pressure of mice treated with GsMTx4 (1mg / kg) decreased significantly (P<0.05). This shows that GsMTx4 can alleviate the increase in blood pressure caused by plateau hypoxia.

[0064] b. Figure 2 It showed that after 3 and 7 days of feeding mice in a hypobaric oxygen chamber (simulating an altitude of 6000m), the heart rate of mice increased, and the increase in heart rate was more obvious on the 7th day. After intraperitoneal injection of GsMTx4 (1mg / kg) into mice, the heart rate of mice decreased more significantly (P<0.05), indicating that GsMTx4 can alleviate the increase in heart rate caused by plateau hypoxia.

[0065] c. Figure 3 It indicates that after 3 and 7 days of feeding mice in a hypobaric oxygen chamber (simulating an altitude of 6000m), the weight of the mice decreased, and the weight loss was more obvious on the 7th day. After intraperitoneal injection of mice with GsMTx4 (1mg / kg), there was no significant change in the weight of the mice.

[0066] d. Changes in endothelial function in mice

[0067] Figure 4 It means that after the mice were kept in a hypobaric oxygen chamber (simulating an altitude of 6000m) for 7 days, blood was taken from the eyeballs to measure nitric oxide (NO) and endothelin-1 (ET-1) in the mice. The NO and EF-1 of the mice increased, indicating that the endothelial function of the mice was impaired. The increase in NO may be due to the compensatory increase of NO in order to adapt to the hypoxic changes after high altitude hypoxia, thereby dilating blood vessels. After intraperitoneal injection of GsMTx4 into mice, both the serum NO and EF-1 of the mice decreased. This shows that GsMTx4 can alleviate the endothelial cell damage caused by high altitude hypoxia.

[0068] f.See Figure 5It is indicated that the mouse aorta tissue was sliced ​​and the difference of Piezo1 and LC3 in the aortic endothelium was detected by fluorescent staining. After hypoxia, the expression of Piezo1 and LC3 in aortic endothelial cells increased, and after the addition of GsMTx4 (1mg / kg), the expression of Piezo1 and LC3 decreased. This shows that under the high altitude environment, the expression of Piezo1 is increased and the mitochondrial autophagy is enhanced, and GsMTx4 can alleviate this damage.

[0069] 2. In vitro experiments: The present invention has preliminarily explored the role of Piezo1 in endothelial cells of high-altitude hypertension: Under high-altitude hypertension conditions, endothelial cell damage may be related to Piezo1 activating BNIP3-mediated mitochondrial autophagy. The specific results are as follows:

[0070] 2-1 A high-altitude hypertension cell model was constructed by stimulating human aortic endothelial cells (HAEC) with hypoxia and pressure. Compared with the control group, the enhancement of Piezo1 in HAEC was most significant under hypoxia and pressure conditions. The cells were stimulated under hypoxia + pressure for different time periods (0h, 12h, 24h, 36h, 48h, respectively), and it was found that mitochondrial autophagy was most obvious 24 hours after cell stimulation. Under the high-altitude hypertension model, Piezo1 overexpression caused calcium ion influx and increased calcium ion concentration in the cytoplasm. Mitochondrial function changed: mitochondrial autophagy was enhanced, mitochondrial membrane potential was reduced, and mitochondrial reactive oxygen species were increased. Endothelial cell function changed: cell proliferation activity was reduced, NO was increased, and ET-1 levels were increased.

[0071] (1) Expression of Piezo1 in HAEC cells after hypoxia + pressure simulated plateau conditions

[0072] like Figure 6 As shown, HAEC were divided into the following 4 groups: control group, hypoxia group, pressure group and hypoxia + pressure group. Western blot showed that after the hypoxia + pressure group simulated high-altitude hypertension conditions, the increase of Piezo1 in human aortic endothelial cells was the most obvious compared with the control group, and correspondingly, the change of mitochondrial autophagy was also the most obvious (the increase of BNIP3 and LC3 was the most obvious).

[0073] (2) Changes in mitochondrial autophagy in HAEC

[0074] like Figure 7 As shown, Western blot showed that after hypoxic pressure simulated high-altitude hypertension conditions, compared with the control group, mitochondrial autophagy showed different trends as the stimulation time changed. The results showed that mitochondrial autophagy was the strongest at the 24th hour.

[0075] (3) Cytoplasmic Ca in HAEC 2+ concentration

[0076] like Figure 8 As shown in the flow cytometry results, compared with the control group, the HAEC cytoplasmic Ca 2+ Concentration increased.

[0077] (4) Mitochondrial membrane potential in HAEC

[0078] like Fig. 9 As shown in Figure a: Confocal results showed that compared with the control group, the mitochondrial membrane potential (JC-1) of the hypoxic stress group was decreased. Figure b: Flow cytometry results showed that compared with the control group, the mitochondrial membrane potential (JC-1) of the hypoxic stress group was decreased.

[0079] (5) Increased mitochondrial ROS content in HAEC

[0080] like Fig.10 As shown, flow cytometry results showed that the concentration of HAEC cytoplasmic ROS increased in the hypoxic stress group compared with the control group.

[0081] (6) Changes of ET-1 in HAEC

[0082] like Fig.11 As shown, compared with the control group, Figure a shows that the NO concentration in the hypoxic stress group was reduced, and Figure b shows that the ET-1 concentration in the hypoxic stress group was increased.

[0083] (7) Changes in HAEC proliferation and migration

[0084] like Fig.12 As shown, the Transwell migration experiment showed that the number of HAEC migration in the normoxic group and the hypoxic stress group was 217.3±11.73 and 392.7±19.8, respectively. Compared with the control group, the number of HAEC migration in the hypoxic stress group increased (Figure a). The CCK8 experiment showed that the cell proliferation activity increased (Figure b).

[0085] 2-2 After stimulating the cells with Piezo1 agonist (Yoda1) and inhibitor (GsMTx4), the changes in human aortic endothelial cells were observed. Under hypoxia + stress conditions, after adding Piezo1 agonist (Yoda1), WB showed enhanced mitochondrial autophagy, and immunofluorescence showed an increase in autophagosomes and lysosomes. After adding Piezo1 inhibitor (GsMTx4), WB showed weakened mitochondrial autophagy, and immunofluorescence showed weakened autophagosomes and lysosomes. This shows that GsMTx4 can alleviate the enhanced mitochondrial autophagy caused by plateau stress.

[0086] Under hypoxia + stress conditions, changes in mitochondrial function were observed: after adding the Piezo1 agonist (Yoda1), ROS increased, mitochondrial membrane potential decreased, and ATP decreased. After adding the Piezo1 inhibitor (GsMTx4), ROS decreased, mitochondrial membrane potential increased, and ATP increased, indicating that the Piezo1 inhibitor can alleviate the changes in mitochondrial function caused by high altitude stress.

[0087] Under hypoxia + pressure conditions, changes in endothelial cell function were observed: after adding the Piezo1 agonist (Yoda1), ET-1 increased, NO decreased, and Transewell showed enhanced cell migration ability. After adding the Piezo1 inhibitor (GsMTx4), ET-1 decreased, NO increased, and Transewell showed weakened cell migration ability. This shows that the Piezo1 inhibitor can alleviate the endothelial cell function damage caused by high altitude pressure.

[0088] (8) Effect of Piezo1 on mitochondrial autophagy

[0089] like Fig.13 As shown, Figure a shows that western blot results show that under hypoxic stress conditions, after the addition of Piezo1 agonist (Yoda1), BNIP3 increased, FOXO3a increased, LC3Ⅱ / LC3Ⅰ increased, and Tom20 decreased. After the addition of Piezo1 inhibitor (GsMTx4), FOXO3a decreased, BNIP3 decreased, LC3Ⅱ / LC3Ⅰ decreased, and Tom20 increased. Figure b shows that under hypoxic stress conditions, after the addition of Piezo1 agonist (Yoda1), mitochondrial lysosomes increased, and after the addition of Piezo1 inhibitor (GsMTx4), mitochondrial lysosomes decreased.

[0090] (9) Piezo1 to Ca 2+ Impact

[0091] like Fig.14 As shown, flow cytometry results showed that after adding Piezo1 agonist (Yoda1), HAEC cytoplasmic Ca 2+ After adding Piezo1 inhibitor (GsMTx4), HAEC cytoplasmic Ca 2+ The concentration decreases.

[0092] (10) Effects of Piezo1 on mitochondrial function

[0093] like Fig.15As shown, the flow cytometry results showed that compared with the control group, ROS increased after the addition of Piezo1 agonist (Yoda1). After the addition of Piezo1 inhibitor (GsMTx4), ROS decreased (Figure a). After the addition of Piezo1 agonist (Yoda1), mitochondrial membrane potential decreased, and after the addition of Piezo1 inhibitor (GsMTx4), mitochondrial membrane potential increased (Figure b). After the addition of Piezo1 agonist (Yoda1), ATP decreased, and after the addition of Piezo1 inhibitor (GsMTx4), ATP increased (Figure c).

[0094] (11) Effects of Piezo1 on endothelial cells

[0095] like Fig.16 As shown, compared with the control group, after the addition of Piezo1 agonist (Yoda1), the flow cytometry results showed that NO decreased, and after the addition of Piezo1 inhibitor (GsMTx4), the flow cytometry results showed that NO increased (Figure a). Transwell showed that after the addition of Piezo1 agonist (Yoda1), cell migration increased, and after the addition of Piezo1 inhibitor (GsMTx4), cell migration decreased (Figure b). Compared with the control group, after the addition of Piezo1 agonist (Yoda1), the flow cytometry results showed that ET-1 increased, and after the addition of Piezo1 inhibitor (GsMTx4), the flow cytometry results showed that ET-1 decreased (Figure c).

[0096] 2-3 Under hypoxia + pressure (hereinafter referred to as hypoxia group) conditions, after knocking down BNIP3, the changes of human aortic endothelial cells were observed.

[0097] (12) Changes in mitochondrial autophagy after knockdown of BNIP3, such as Fig.17 As shown, qPCR showed that HAEC knocked down BNIP3 (Figure a), and Western blot showed that mitochondrial autophagy was weakened after knocking down BNIP3 under hypoxic conditions compared with the hypoxia group (Figure b).

[0098] (13) Changes in mitochondrial function after knockdown of BNIP3, such as Fig.18 As shown, after knocking down BNIP3 under hypoxia, compared with the hypoxia group, mitochondrial membrane potential increased (Figure a), ROS decreased (Figure b), and ATP increased (Figure c). This indicates that knocking down BNIP3 can alleviate mitochondrial function damage caused by hypoxia.

[0099] (14) Changes in cell function after knockdown of BNIP3, such as Fig.19As shown, after knocking down BNIP3 in a hypoxic environment, compared with the hypoxia group, endothelial cell NO increased (Figure a), ET-1 decreased (Figure b), and Transewell showed that cell migration ability was weakened (Figure c). This shows that knocking down BNIP3 can alleviate the damage to endothelial cell function caused by hypoxia.

[0100] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. Application of Piezo1 inhibitors in the preparation of drugs for the treatment of high-altitude hypertension.

2. The use according to claim 1, characterized in that: The Piezo1 inhibitor is a substance that inhibits Piezol activity or a substance that reduces Piezol levels; the substance that inhibits Piezol activity is selected from GsMTx4, thapsigargin or cytochalasin D, and the substance that inhibits Piezol activity is a GsMTx4 polypeptide, the sequence of which is shown below: Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Ly s-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe-NH2.

3. The use according to claim 1, characterized in that: The dosage of the Piezo1 inhibitor is 0.5-1.5 mg / kg, preferably, the dosage of the Piezo1 inhibitor is 1 mg / kg.

4. Application of Piezo1 inhibitors in the preparation of drugs for the treatment of vascular endothelial damage caused by high-altitude hypertension.

5. The use according to claim 4, characterized in that: The Piezo1 inhibitor is a substance that inhibits Piezol activity or a substance that reduces Piezol levels; preferably, the substance that inhibits Piezol activity is selected from GsMTx4, thapsigargin or cytochalasin D; The substance that inhibits Piezol activity is GsMTx4 polypeptide, and its sequence is as follows: Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Ly s-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe-NH2; The dosage of the Piezo1 inhibitor is 0.5-1.5 mg / kg, preferably, the dosage of the Piezo1 inhibitor is 1 mg / kg.

6. Application of BNIP3 inhibitors in the preparation of drugs for the treatment of high-altitude hypertension.

7. Application of BNIP3 inhibitors in the preparation of drugs for treating vascular endothelial damage caused by high-altitude hypertension.

8. A method for improving high-altitude hypertension using GsMTx4 compounds, characterized in that: GsMTx4 compounds are used as Piezo1 inhibitors to regulate cardiovascular endothelial cell damage through BNIP3-mediated mitochondrial autophagy, thereby reducing high-altitude hypertension.

9. A method for improving high-altitude hypertension using GsMTx4 compound according to claim 8, characterized in that: As an inhibitor of the Piezo1 channel, GsMTx4 binds to the cell membrane of endothelial cells in the cardiovascular system, enters the lipid bilayer by inserting its hydrophobic domain, directly acts on the membrane of the backbone protein, blocks the mechanical force, and transmits it by changing the tension of the membrane, thereby achieving the blockade of the Piezo1 ion channel.

10. A method for improving high-altitude hypertension using GsMTx4 compound according to claim 8, characterized in that: At altitudes above 3000 meters, Piezo1 in cardiovascular endothelial cells is stimulated by pressure, and the channel opens, causing Ca 2+ Influx, excessive Ca 2+ Influx of Ca induces changes in FOXO3a, which in turn regulates BNIP3-mediated mitochondrial autophagy. 2+ Influx promotes mitochondrial dysfunction, ultimately causing endothelial cell damage, thereby increasing blood pressure; using GsMTx4 as an inhibitor of the Piezo1 channel can reverse endothelial cell damage in the cardiovascular system, thereby reversing the formation of plateau hypertension.

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