Aortic aneurysm treatment target and application thereof

Abstract

The invention relates to an aortic aneurysm treatment target spot and application thereof, and belongs to the technical field of biological medicine. The invention finds that the CALHM5 is highly expressed in the aorta and is relatively low in expression level in the heart for the first time, so that the drug targeting the CALHM5 has fewer heart side effects. In addition, a calcium ion induced abdominal aortic aneurysm model is constructed based on a CALHM5 whole body knockout mouse and a CALHM5 vascular smooth muscle specific knockout mouse respectively; it is found that down-regulation of expression of the CALHM5 can increase the retention amount of intima vascular smooth muscle cells of the abdominal aortic aneurysm, reduce the elastic fiber fracture degree and maintain the inner diameter of a blood vessel at an injured part at a small level, so that function deficiency of the CALHM5 can significantly weaken tension of the aorta, retention of the intima vascular smooth muscle of the abdominal aortic aneurysm is promoted, and the abdominal aortic aneurysm is inhibited. The effect of slowing down the development of aortic aneurysm is achieved. Therefore, the CALHM5 can be used as a treatment target of the aortic aneurysm, and a direction is pointed out for subsequent treatment of the aortic aneurysm.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to a treatment target for aortic aneurysm and its application. Background Art

[0002] Aortic aneurysm is a local or diffuse abnormal dilation of the aortic wall. When the aneurysm continues to grow and exceeds the pressure limit that the aorta can withstand, it will rupture, leading to massive internal bleeding and endangering life in a short time, with a mortality rate as high as over 80%. Currently, aortic aneurysm is mainly treated by a combination of drug therapy and surgical treatment when necessary. At present, there is no specific drug that can completely prevent the progression of aortic aneurysm. Developing new drug targets for aortic aneurysm has important clinical significance. The common sites of aortic aneurysm include the thoracic aorta, abdominal aorta, and descending aorta, and its formation causes are diverse, mainly including atherosclerosis, cystic necrosis of the middle layer of blood vessels, syphilis infection, bacterial infection, rheumatic aortitis, and trauma, etc.

[0003] The main goal of drug treatment for aortic aneurysm is to control related risk factors, such as hypertension, hyperlipidemia, etc., to slow down the dilation rate of aortic aneurysm and reduce the rupture risk. At the same time, drug treatment also helps to relieve the symptoms of patients and improve the quality of life. Currently, the commonly used drugs for treating aortic aneurysm on the market mainly include: β-blockers, which can inhibit the activity of sympathetic nerves, reduce myocardial contractility and heart rate, reduce the pressure and tension on the aortic wall, and help delay the progression of aneurysm; antihypertensive drugs, which can reduce peripheral resistance, improve vascular endothelial function, help prevent the rupture of aortic aneurysm, or effectively control blood pressure and reduce the pressure on the aortic wall through mechanisms such as vasodilation and blood volume reduction; statins, which can regulate blood lipids, have anti-inflammatory and atherosclerotic plaque-stabilizing effects, help improve the vascular endothelial function of aortic aneurysm patients, and slow down the development of aneurysm; antiplatelet drugs, which can inhibit platelet aggregation, prevent thrombosis, and reduce the risk of complications caused by thrombosis in aortic aneurysm patients.

[0004] Among antihypertensive drugs, calcium channel blocker drugs targeting L-type calcium channels have become an important treatment method because they can effectively reduce blood pressure, reduce the pressure load on the aortic wall, and thus slow down the dilation rate of aortic aneurysm. Calcium channel blockers block the calcium channels on vascular smooth muscle cells, reduce the influx of calcium ions, and thus reduce the tension of vascular smooth muscle, achieving a significant antihypertensive effect. This is of great significance for controlling the blood pressure level of aortic aneurysm patients and reducing the risk of aneurysm rupture. For example, the patent with the application number WO2022US18501 combines folic acid complex with the calcium channel blocker nifidipine for the treatment of aortic aneurysm.

[0005] Currently, calcium channel blockers have serious side effects in the treatment of aortic aneurysms. Common side effects include headache, facial flushing, palpitations, lower extremity edema, etc. In addition, long-term use of calcium channel blockers may also affect physiological processes such as blood lipid and blood glucose metabolism, increasing the risk of cardiovascular diseases. Moreover, the drugs for treating calcium channel blockers basically act on the L-type calcium channel, and the L-type calcium channel is not only expressed in arteries but also plays an indispensable role in the cardiac pumping process. Calcium channel blockers can inhibit the calcium ion concentration in cardiomyocytes, thereby reducing the contractility of the myocardium. For patients with heart failure, this side effect may be particularly obvious and may even exacerbate heart failure symptoms. Calcium channel blockers may also affect the function of the cardiac conduction system, leading to arrhythmias such as atrioventricular block, which is more common in non-dihydropyridine calcium channel blockers. Therefore, there is an urgent need to seek a drug target for aortic aneurysms with fewer side effects. Summary of the Invention

[0006] To this end, the technical problem to be solved by the present invention is to overcome the problem of many side effects of the existing treatment targets for aortic aneurysms.

[0007] To solve the above technical problems, the present invention provides a treatment target for aortic aneurysms and its application. The present invention first discovers that CALHM5 is highly expressed in the aorta and has a relatively low expression level in the heart. Therefore, drugs targeting CALHM5 have fewer cardiac side effects. The present invention also discovers that the expression level of CALHM5 decreases in patients with abdominal aortic aneurysms. In order to explore whether the decrease in CALHM5 leads to the occurrence of aortic aneurysms or whether the decrease in CALHM5 expression in abdominal aortic aneurysms is a self-protective mechanism of the body, the present invention also constructs a calcium ion-induced abdominal aortic aneurysm model based on CALHM5 knockout mice and CALHM5 vascular smooth muscle-specific knockout mice respectively, and finds that the abdominal aortic aneurysm models with global CALHM5 knockout and CALHM5 vascular smooth muscle-specific knockout show similar results. Down-regulating the expression of CALHM5 can increase the retention of vascular smooth muscle cells in the media layer, reduce the degree of elastic fiber fracture, and maintain the vascular inner diameter at a smaller level at the damaged site. Therefore, the loss of CALHM5 function can significantly weaken the aortic tension, promote the retention of smooth muscle in the media layer of abdominal aortic aneurysms, and play a role in slowing down the development of aortic aneurysms. Therefore, the decrease in CALHM5 expression in aortic aneurysms is a self-protective mechanism of the body, and CALHM5 can be used as a treatment target for aortic aneurysms to strengthen this self-protective mechanism, indicating the direction for the subsequent treatment of aortic aneurysms.

[0008] The first object of the present invention is to provide a treatment target for aortic aneurysms, and the treatment target for aortic aneurysms is calcium homeostasis modulator 5.

[0009] Furthermore, the amino acid sequence of the calcium homeostasis regulator 5 is as shown in SEQ ID NO.1.

[0010] Furthermore, the sequence of SEQ ID NO.1 is as follows:

[0011] MDAFQGILKFFLNQKTVIGYSFMALLTVGSERLFSVVAFKCPCSTENMTYGLVFLFAPAWVLLILGFFLNNRSWRLFTGCCVNPRKIFPRGHSCRFFYVLGQITLSSLVAPVMWLSVALLNGTFYECAMSGTRSSGLLELICKGKPKECWEELHKVSCGKTSMLPTVNEELKLSLQAQSQILGWCLICSASFFSLLTTCYARCRSKVSYLQLSFWKTYAQKEKEQLENTFLDYANKLSERNLKCFFENKR

[0012] The second object of the present invention is to provide an application of the calcium homeostasis regulator 5 in the preparation of a medicament for treating aortic aneurysm, and the medicament can reduce the expression level of the calcium homeostasis regulator 5.

[0013] The third object of the present invention is to provide an application of an inhibitor of the calcium homeostasis regulator 5 in the preparation of a therapeutic product for aortic aneurysm.

[0014] Furthermore, the action site of the therapeutic product for aortic aneurysm is vascular smooth muscle.

[0015] Furthermore, the dosage form of the therapeutic product for aortic aneurysm is a solid dosage form or a liquid dosage form.

[0016] The fourth object of the present invention is to provide an aortic aneurysm marker, and the aortic aneurysm marker is the calcium homeostasis regulator 5.

[0017] The fifth object of the present invention is to provide an application of the calcium homeostasis regulator 5 in the preparation of a detection kit for aortic aneurysm.

[0018] The sixth object of the present invention is to provide an application of a reagent for detecting the expression level or secretion level of the calcium homeostasis regulator 5 in the preparation of a kit for diagnosing aortic aneurysm.

[0019] The beneficial effects of the present invention:

[0020] The present invention provides a treatment target for aortic aneurysm and its application. The present invention discovers for the first time that CALHM5 is highly expressed in the aorta and has a relatively low expression level in the heart. Therefore, drugs targeting CALHM5 have fewer cardiac side effects compared to commonly used calcium channel blockers. In addition, through the abdominal aortic aneurysm modeling of CALHM5 global knockout mice and the abdominal aortic aneurysm modeling of CALHM5 vascular smooth muscle-specific knockout mice, the present invention shows that CALHM5 is highly expressed in smooth muscle cells of the aortic media layer, and downregulating the expression of CALHM5 can increase the retention of vascular smooth muscle cells in the media layer, reduce the degree of elastic fiber fracture, and maintain the vascular inner diameter at a smaller level at the injury site. The loss of function of CALHM5 can significantly weaken the aortic tension, reduce blood pressure, promote the retention of smooth muscle in the abdominal aortic aneurysm media layer, and play a role in slowing down the development of aortic aneurysm. Therefore, CALHM5 can be used as a treatment target for aortic aneurysm, indicating the direction for subsequent treatment of aortic aneurysm. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to make the content of the present invention easier to be clearly understood, the following further details the present invention according to specific embodiments of the present invention in combination with the drawings, where

[0022] Figure 1 is the research idea of CALHM5 as a new drug target for the prevention and treatment of aortic aneurysm;

[0023] Figure 2 is the expression of CALHM5 in different databases; A. The mRNA expression level of human Calhm5 in different tissues and organs in the GTEx Portal database; B. The protein level of human CALHM5 in different tissues and organs in the TSomics database; C. The mRNA level of Calhm5 in different tissues and organs of mice;

[0024] Figure 3 is the mRNA expression level of Calhm5 in patients with abdominal aortic aneurysm and mouse models in the GEO database; A - B. Human Calhm5 expression data from GSE57691 (A) and GSE7084 (B); C - D. Mouse Calhm5 expression in a mouse aortic dissection model (C, GSE215935) and a porcine pancreatic elastase (PPE)-induced abdominal aortic aneurysm (AAA) model (D, GSE57691);

[0025] Figure 4 is the verification electrophoresis pattern of Calhm5 gene global knockout mice;

[0026] Figure 5It is a mouse model of abdominal aortic aneurysm with systemic knockout of the Calhm5 gene induced by calcium; (A) Representative images of frozen sections of AAA tissues stained with hematoxylin-eosin; (D) Statistics of the inner diameter of aneurysms in representative images of frozen sections of AAA tissues stained with hematoxylin-eosin, scale bar, 80 μm; (B) Representative images of elastic fibers stained with Victoria blue; (E) Elastic protein degradation score, scale bar, 80 μm; (C) Representative immunofluorescence staining of the vascular smooth muscle marker α-SMA; (F) Statistics of the α-SMA positive area, scale bar, 200 μm;

[0027] Figure 6 It is a schematic diagram of a mouse with specific knockout of Calhm5 in vascular smooth muscle cells; The Flox mouse is a mouse with LoxP sites inserted on both sides of the Calhm5 gene. On this basis, the CKO mouse introduced the Cre enzyme specifically expressed in vascular smooth muscle cells. The Cre enzyme cuts the Calhm5 gene in the middle of the LoxP site to achieve the effect of specifically knocking out Calhm5 in vascular smooth muscle cells;

[0028] Figure 7 It is the verification result of specific knockout of Calhm5 in vascular smooth muscle cells, where VSMC represents vascular smooth muscle cells and AF represents fibroblasts;

[0029] Figure 8 It is the electrophoresis pattern of mice with specific knockout of Calhm5 in vascular smooth muscle cells;

[0030] Figure 9 It is a mouse model of abdominal aortic aneurysm with specific knockout of the Calhm5 gene in vascular smooth muscle induced by calcium; (A) Representative images of frozen sections of AAA tissues stained with hematoxylin-eosin; (D) Statistics of the inner diameter of aneurysms, scale bar, 80 μm (B) Representative images of elastic fibers stained with Victoria blue; (E) Elastic protein degradation score (E), scale bar, 80 μm; (C) Representative immunofluorescence staining of the vascular smooth muscle marker α-SMA; (F) Statistics of the α-SMA positive area, scale bar, 200 μm. Specific embodiments

[0031] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the embodiments cited do not limit the present invention.

[0032] Example 1: Expression of CALHM5 in different organs

[0033] First, retrieve the human mRNA (GTEx Portal database) and protein (TSomics database) databases ( Figure 2.(A-B), then anesthetize wild-type mice and open the thoracic and abdominal cavities. Cut out the heart, liver, spleen, lungs, kidneys, brain, small intestine, and aorta. Immerse the tissues in liquid nitrogen and grind them at low temperature. Collect the dry powder and use a kit to extract mRNA and perform reverse transcription. After obtaining cDNA, perform quantitative real-time PCR (qPCR) (the primer sequences are shown in Table 1) for verification ( Figure 2 .(C), thus determining that CALHM5 is highly expressed in aortic smooth muscle and has a relatively low expression level in the heart.

[0034] By querying the vascular disease GEO database, it was found that CALHM5 was downregulated in multiple abdominal aortic aneurysm databases ( Figure 3 ).

[0035] Table 1 Primers and their sequences involved in Example 1

[0036] SEQ ID Primer Name Sequence SEQ ID NO.2 Forward CCAAAGAGTGCTGGGAAGAACTG SEQ ID NO.3 Reverse ACGCCGAACAAATCAGGCACCA

[0037] Example 2: Verification of abdominal aortic aneurysm modeling based on the Calhm5 knockout mouse (KO) model

[0038] 1. Construction of the Calhm5 knockout mouse (KO) model

[0039] The Calhm5 knockout mice were constructed using the Bio-Cell Extreme Genome Editing System ( system) at Jicui Pharmaceutical Co., Ltd. According to the gene sequence Calhm5 encoding CALHM5 in C57BL / 6JGpt mice, two sgRNA sequences were designed and synthesized (the sequence of sgRNA1 is shown as SEQ ID NO.4, and the sequence of sgRNA2 is shown as SEQ ID NO.5), resulting in a chromosomal deletion of approximately 3.0 kb at the EGE-LZL-030-A site in the mouse genome.

[0040] Table 2 Primers and their sequences used in Example 2

[0041] Sequence Number Primer Name Sequence SEQ ID NO.4 sgRNA 1 AAGTGTAAGAAGCTTCGCCTAGG SEQ ID NO.5 sgRNA 2 GGGGACAATAGCACCTATTGTGG

[0042] Healthy C57BL / 6JGpt mice were selected as egg donors. The C57BL / 6JGpt mice were intraperitoneally injected with PMSG (pregnant mare serum gonadotropin), and 48 h later, hCG (human chorionic gonadotropin) was injected. Immediately afterwards, they were mated with normal fertile C57BL / 6JGpt male mice. Mouse fertilized eggs were collected, digested and washed, and then placed in an incubator at 37 °C for later use. The Cas9 protein-encoding gene and the synthetic sgRNA1 and sgRNA2 were mixed and microinjected into the nuclei of mouse fertilized eggs, and then transplanted into the ampulla of the oviduct of surrogate mother mice. The surrogate mother mice were weighed every other week to preliminarily determine pregnancy. The pups were delivered 19 - 21 days after the operation to obtain F0 generation mice. The genotypes of the F0 generation mice were identified, and F0 positive mice were screened.

[0043] The F0 positive mice were mated with wild-type C57BL / 6JGpt mice to obtain F1 generation mice that could be stably inherited. The F1 generation mice were screened and identified as CALHM5 global knockout mice (KO).

[0044] Identification of Calhm5 global knockout mice (KO):

[0045] (1) Genomic DNA was extracted from the tails of mice. The kit used was the Tiangen DP304 centrifugal column type genomic DNA extraction kit.

[0046] (2) Calhm5 global knockout mice (KO):

[0047] Prepare the mixture: the genomic DNA solution prepared in step (1), PCR buffer, dNTP, Taq DNA polymerase, primers and pure water; PCR conditions: 98 °C for 5 minutes, 98 °C for 30 seconds, 60 °C for 30 seconds, 72 °C for 45 seconds, 72 °C for 8 minutes, for 30 cycles, and the reaction was completed. The PCR primer sequences were downloaded from www.ncbi.nlm.nih.gov / for the Calhm5 gene sequence, and primers were designed and synthesized based on the downloaded Calhm5 gene sequence (as shown in Table 3). Calhm5 global knockout mice (KO) showed a 604 bp band, wild-type mice (WT) showed a 708 bp band, and heterozygous mice (HET) showed 604 and 708 bp bands. The electrophoresis pattern is shown in Figure 4 。

[0048] Table 3 Primers used to identify KO mice

[0049] Sequence Number Sequence Name Sequence SEQ ID NO.6 <![CDATA[Calhm5 + -F]]> GCAGTTTAGGACTCACTTCGTTTTG SEQ ID NO.7 <![CDATA[Calhm5 +- R]]> cggcatggtgtttcataccagaaca SEQ ID NO.8 <![CDATA[Calhm5 - -F]]> GCAGTTTAGGACTCACTTCGTTTTG SEQ ID NO.9 <![CDATA[Calhm5 - -R]]> TCCTCTACCTCAGATAATCCTGATG

[0050] (2) Establishment of abdominal aortic aneurysm models based on Calhm5 global knockout mice (KO)

[0051] Wild-type and Calhm5 global knockout mice (KO) at 9-12 weeks of age were selected, with their body weights controlled at 22-26 g. For each genotype, a sham operation group and a modeling group were set up. An abdominal aortic aneurysm model was established by applying CaCl 2 and 10×PBS to produce calcium phosphate deposition at the abdominal aorta. In the sham operation group, sodium chloride was used instead of calcium phosphate, and the others were exactly the same. The specific steps were as follows: Open the abdominal cavity of the mice, remove the protective tissues around the blood vessels, apply a gauze strip soaked in 0.05M CaCl 2 to the exposed abdominal aorta of the mice for 10 minutes, apply a gauze strip soaked in 10×PBS solution for 5 minutes, wash with normal saline containing penicillin-streptomycin, suture the wound, and perform the next detection two weeks later. Stain the tissue sections of the abdominal aortic aneurysm, and the experimental results are as Figure 5 shown. Figure 5 A. After detecting the size of the abdominal aortic aneurysm by hematoxylin-eosin staining kit, it was found that the inner diameter of the aneurysm blood vessels in Calhm5 knockout mice was significantly smaller. Figure 5 B. After detecting the rupture of elastic fibers by Victoria blue staining kit, it was found that the symptoms of elastic fiber rupture in Calhm5 knockout mice were significantly milder. Figure 5 C. By immunofluorescence staining with an antibody against the smooth muscle marker protein α-SMA to detect the loss of the aortic media layer, it was found that the loss of the media layer in Calhm5 knockout mice was significantly less. In summary, global knockout of Calhm5 alleviated the symptoms of abdominal aortic aneurysm ( Figure 5 ).

[0052] Example 3: Verification of abdominal aortic aneurysm modeling based on Calhm5 vascular smooth muscle-specific knockout mice (CKO)

[0053] 1. Construction of Calhm5 vascular smooth muscle-specific knockout mice (CKO)

[0054] The construction of Calhm5 vascular smooth muscle-specific knockout mice was achieved through the Cre / LoxP system. Flox mice were mated with Acta2-iCre mice that specifically expressed Cre recombinase in vascular smooth muscle to obtain Flox / Cre+ mice (Flox mice were provided by Jicui Pharmaceutical Co., Ltd. [C57BL / 6JGpt-Fam26eem1Cflox / Gpt]; Acta2-iCre mice were also provided by Jicui Pharmaceutical Co., Ltd. [C57BL / 6JGpt-Tg(Acta2-iCre-polya)62 / Gpt]). Cre recombinase was expressed in Flox / Cre+ mice, thereby recombining the sequence between the loxP sites in Flox / Cre + mice, that is, the sequence between the loxP sites in Flox / Cre +Knock out the CALHM5 gene in mouse smooth muscle, which inhibits the function of the CALHM5 gene, thereby obtaining a mouse with smooth muscle-specific knockout of the Calhm5 gene, which is denoted as CKO. Figure 6 It is a strategy for conditional knockout of the Calhm5 gene.

[0055] Identification of Calhm5 smooth muscle-specific knockout mice (CKO):

[0056] (1) Extract genomic DNA from the mouse tail. The kit used is the Tiangen DP304 centrifugal column type genomic DNA extraction kit.

[0057] (2) Calhm5 smooth muscle-specific knockout mice (CKO):

[0058] Add the genomic DNA solution prepared in step (1), PCR buffer, dNTP, Taq DNA polymerase, primers, and pure water; PCR conditions: 5 minutes at 98°C, 30 seconds at 98°C, 30 seconds at 60°C, 45 seconds at 72°C, 8 minutes at 72°C, for 30 cycles, and the reaction is completed. The PCR primer sequences are downloaded from the CALHM5 gene sequence on www.ncbi.nlm.nih.gov / and primers are designed and synthesized according to the downloaded Calhm5 gene sequence (as shown in Table 3). Run the prepared samples on an agarose gel to confirm the size.

[0059] In the presence of the Cre gene, it expresses Cre recombinase. Cre recombinase can recognize two Loxp sites anchored at both ends of CALHM5, and under its action, excise the CALHM5 sequence between the two LoxP sites, thereby achieving knockout of the CALHM5 gene. Primers Flox-F and Flox-R bind to both sides of the loxP site respectively to identify the presence of the LoxP site. The target genotype band is 425bp. Cre is identified with Acta2-iCre-F and Acta2-iCre-R, and the target genotype band is 361bp ( Figure 8 ). The specifically knockout mice are detected by qRT-PCR using vascular smooth muscle cells and vascular fibroblast samples. By detecting the expression of CALHM5 in aortic smooth muscle cells (VSMC) and fibroblasts (AF), the expression of CALHM5 in VSMC is significantly decreased, while there is no change in AF, indicating that the Calhm5 smooth muscle-specific knockout mice have been successfully constructed ( Figure 7 ).

[0060] Table 4 Primers used for the identification of Calhm5 smooth muscle-specific knockout mice (CKO)

[0061] Sequence Number Sequence Name Sequence SEQ ID NO.10 Flox-F TTGCCCAGCTTCCCGAAAA SEQ ID NO.11 Flox-R ccaccacccggctgctaacatat SEQ ID NO.12 Acta2-iCre-F ACTCCCGCTCTTTGTGCTGAG SEQ ID NO.13 Acta2-iCre-R CTTCATCAGAGGTGGCATCCA

[0062] (2) Establishment of abdominal aortic aneurysm model in Calhm5 vascular smooth muscle-specific knockout mice (CKO)

[0063] Wild-type and Calhm5 vascular smooth muscle-specific knockout mice at 9 - 12 weeks of age, with body weight controlled at 22 - 26 g, were selected. For each genotype, a sham operation group and a model group were set up. An abdominal aortic aneurysm model was established by applying CaCl 2 and 10×PBS to produce calcium phosphate deposition in the abdominal aorta. In the sham operation group, sodium chloride was used instead of calcium phosphate, and the others were exactly the same. The specific steps were as follows: Open the abdominal cavity of the mice, remove the protective tissues around the blood vessels, apply a gauze strip soaked in 0.05M CaCl 2 to the exposed abdominal aorta of the mice for 10 minutes, apply a gauze strip soaked in 10×PBS solution for 5 minutes, wash with normal saline containing penicillin - streptomycin, suture the wound, and perform the next detection two weeks later. Stain the tissue sections of the abdominal aortic aneurysm, and the experimental results are as Figure 9 shown. Figure 9 In A, the size of the abdominal aortic aneurysm was detected by hematoxylin - eosin staining kit, and it was found that the inner diameter of the aneurysm - formed blood vessels in CALHM5 knockout mice was significantly smaller. Figure 9 In B, the fracture of elastic fibers was detected by Victoria blue staining kit, and it was found that the symptoms of elastic fiber fracture in CALHM5 knockout mice were significantly milder. Figure 9 In C, the loss of the aortic media layer was detected by immunofluorescence staining using an antibody against smooth muscle marker protein α - SMA, and it was found that the loss of the media layer in CALHM5 knockout mice was significantly less. In summary, the knockout of Calhm5 in vascular smooth muscle alleviated the symptoms of abdominal aortic aneurysm( Figure 9 ).

[0064] Mice with Calhm5 vascular smooth muscle-specific knockout showed a trend consistent with that of global knockout. CALHM5 was highly expressed in smooth muscle cells of the aortic media layer, and down - regulating the expression of CALHM5 could increase the retention of vascular smooth muscle cells in the media layer, reduce the degree of elastic fiber fracture, and maintain the inner diameter of the blood vessels at the damaged site at a smaller level. The significant changes in the above - mentioned characteristics suggest that down - regulating CALHM5 can alleviate the severity of abdominal aortic aneurysm, and CALHM5 can be an important regulatory target for the prevention and treatment of abdominal aortic aneurysm.

[0065] Obviously, the above - mentioned embodiments are only examples for clear illustration and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. An aortic aneurysm treatment target, characterized in that: The aortic therapeutic target is calcium homeostasis regulatory protein 5.

2. The aortic aneurysm treatment target according to claim 1, characterized in that: The amino acid sequence of the calcium homeostasis regulatory protein 5 is shown in SEQ ID NO.

1.

3. Use of calcium homeostasis regulatory protein 5 in the preparation of a drug for treating aortic aneurysm, characterized in that: The aortic aneurysm treatment drug targets calcium homeostasis regulatory protein 5.

4. The use according to claim 3, characterized in that: The aortic aneurysm treatment drug can reduce the expression level of calcium homeostasis regulatory protein 5.

5. Application of calcium homeostasis regulatory protein 5 inhibitors in the preparation of aortic aneurysm treatment products.

6. The use according to claim 5, characterized in that: The site of action of the aortic aneurysm treatment product is smooth muscle.

7. The use according to claim 5, characterized in that: The dosage form of the aortic aneurysm treatment product is a solid dosage form or a liquid dosage form.

8. An aortic aneurysm marker, characterized in that: The aortic aneurysm marker is calcium homeostasis regulatory protein 5.

9. Application of calcium homeostasis regulatory protein 5 in the preparation of aortic aneurysm detection kit.

10. Use of a reagent for detecting the expression level of calcium homeostasis regulatory protein 5 in the preparation of a kit for diagnosing aortic aneurysm.

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