CN116036233A - Application of small molecular compound PMX53 in preparation of medicines for inhibiting vascular calcification and vascular fibrosis - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a small molecular compound PMX53 in preparation of a medicament for inhibiting vascular calcification and vascular fibrosis. In order to overcome the problems that VC and VF cause higher incidence and mortality of cardiovascular diseases and lack of effective and low-cost clinical medicines, the invention discovers that PMX53 can obviously inhibit VSMCs from osteogenic transdifferentiation and COL1α1 expression, thereby delaying the progress of VC and VF. The mechanism of action of PMX53 in regulating VC and VF may be related to its inhibition of activation of the endoplasmic reticulum stress pathway PERK-eif2α -ATF4 and thus the inhibition of osteogenic transdifferentiation of VSMCs and expression of COL1 α1. Because PMX53 has remarkable effect of inhibiting VC and VF, better drug safety and pharmacokinetics, low cost, easy acquisition and flexible and various administration modes, the PMX53 is expected to be a candidate drug for resisting VC and VF.

Description

Application of small molecular compound PMX 53 in the preparation of drugs for inhibiting vascular calcification and vascular fibrosis

technical field

The invention belongs to the technical field of medicine, and in particular relates to the application of small molecular compound PMX 53 in the preparation of drugs for inhibiting vascular calcification and vascular fibrosis.

Background technique

Vascular calcification (VC) is the core pathological basis leading to high morbidity and mortality of cardiovascular diseases. VC is an abnormal deposition of calcium phosphate in the vascular wall, mainly in the form of hydroxyapatite. VC lesions can involve the arterial intima and media, leading to increased stiffness of the vessel wall, thereby inducing the occurrence of cardiovascular diseases. In the past few decades, researchers have conducted extensive studies on VC, revealing that the mechanism of VC is not only the result of high phosphorus and high calcium environment, but also a multifactorial and highly regulated active process, Including an imbalance between cellular osteogenic transdifferentiation and anti-calcification signaling.

The pathological change of vascular fibrosis (VF) is the deposition of collagen in the vascular wall, mainly type I collagen. In VF, vascular smooth muscle cells (VSMCs) transdifferentiate towards a synthetic phenotype, being the predominant cells expressing type I collagen, accompanied by increased expression of osteopontin (OPN). VF will increase the stiffness of blood vessel wall and reduce the elasticity of blood vessel wall, which will lead to the occurrence of various cardiovascular diseases. In the hyperadenine hyperphosphatemia (AP) mouse model and hyperphosphorus-induced VSMCs in vitro cell model, in addition to changes in VC, changes in VF were also observed. The core lesion of VC is osteogenic transdifferentiation of VSMCs, manifested by increased expression of osteogenic phenotype-related markers (RUNX2, BMP2, etc.) and decreased expression of contractile phenotype-related markers (SM22α, α-SMA, etc.); Transdifferentiation of VSMCs to a synthetic phenotype resulting in increased expression of type I collagen and OPN (Peng J, Qin C, TianSY, Peng JQ. MiR-93 inhibits the vascular calculation of chronic renal failure by suppression of Wnt/beta-catenin pathway. Int Urol Nephrol2022 54:225-235.; Ren LS, Zhang L, Zhu D, Li T, Wang Q, Yuan XY, Hao LR. KMUP-1 regulates the vascular calculation in chronic renal failure by mediating NO/cGMP/PKG signaling pathway. Life Sci 2020 ;253:117683.;Ouyang L,Su X,Li W,Tang L,Zhang M,Zhu Y,XieC,Zhang P,Chen J,Huang H. ALKBH1-demethylated DNAN6-methyladenine modification triggers vascular calculation via osteogenic reprogramming in chron ickidney disease . J Clin Invest 2021; 131).

Sustained low systemic inflammation, extracellular matrix remodeling, oxidative stress, autophagy, DNA damage, immune system, etc. may all be involved in the process of VC and VF. Although a large number of studies have explored the various pathogenesis of VC and VF, providing certain directions and targets for delaying the progress of this emerging health problem, there is still a lack of effective drugs for the treatment of VC and VF in clinical practice. VSMCs are the main players in VC and VF, and the osteogenic transdifferentiation of VSMCs is a key link in VC, and the synthetic phenotype of VSMCs is the main source of type I collagen. Therefore, inhibiting osteogenic transdifferentiation and type I collagen expression of VSMCs is the key to delaying the progression of VC and VF. VSMCs osteogenic transdifferentiation showed increased expression of osteogenic phenotype-related markers (RUNX2, BMP2, etc.) and decreased expression of contractile phenotype-related markers (SM22α, α-SMA, etc.). The increase in type I collagen synthesis was mainly due to changes in the expression level of type I collagen α1 (COL1α1) detected by western blot detection, Masson staining, and immunohistochemistry. The current research mainly focuses on exploring how transcription factors or transcriptional regulators regulate the expression of RUNX2, BMP2, COL1α1 and other related factors in VSMCs from the epigenetic level, but how to translate them into clinical drugs for the treatment of VC and VF is an intermediate step. There are still many difficulties and challenges, and more basic and preclinical research are needed to further explore. Although a few studies have found that some natural compounds or certain drugs (such as spermidine, gallic acid, metformin, etc.) can delay the process of VC by inhibiting the osteogenic transdifferentiation of VSMCs, MitoQ delays the process of VF by inhibiting the expression of COL1α1. However, there are no specific receptors for the above-mentioned natural compounds or drugs on VSMCs, so the effective utilization of drugs and the specificity of targeting VSMCs cannot be guaranteed. Moreover, the half-life of natural compounds is short, and the effective drug concentration in the body cannot be guaranteed.

In summary, the development of new, efficient, and cheap anti-VC and VF drugs is of great significance for reducing the high morbidity and mortality of cardiovascular diseases.

Contents of the invention

In order to overcome the problem that VC and VF lead to higher morbidity and mortality of cardiovascular diseases and the lack of effective and cheap clinical drugs, the present invention provides a new application of the small molecule compound PMX 53, that is, based on PMX 53 It has good drug safety and strong inhibitory effect on VC and VF, and it is used as a candidate drug for anti-VC and VF.

In order to achieve the above object, the technical solution adopted in the present invention is:

The invention provides the application of the small molecular compound PMX 53 in the preparation of drugs for inhibiting vascular calcification and/or vascular fibrosis.

Preferably, the vascular calcification and/or vascular fibrosis is vascular calcification and/or vascular fibrosis caused by high adenine and high phosphorus.

The present invention finds through research that the small molecular compound PMX 53, as a specific antagonist of C5aR1, can competitively bind to the C5a receptor C5aR1 on the surface of VSMCs with high affinity, and then has a strong inhibitory effect on VC and VF, and can The method achieves an effective drug concentration, has better drug safety, and is cheap and easy to obtain.

Preferably, the inhibition of vascular calcification is inhibition or reduction of osteogenic phenotype transdifferentiation of VSMCs.

Preferably, said inhibiting vascular fibrosis is inhibiting or reducing the expression of COL1α1.

The present invention finds through research that PMX 53 can inhibit VSMCs osteogenic phenotype transdifferentiation and COL1α1 expression, thereby achieving the effect of delaying VC and VF.

Preferably, the inhibition or reduction of osteogenic phenotype transformation of VSMCs is achieved by inhibiting the activation of PERK-eIF2α-ATF4 signaling pathway.

Preferably, said inhibiting or reducing the expression of COL1α1 is achieved by inhibiting the activation of PERK-eIF2α-ATF4 signaling pathway.

Further research in the present invention found that PMX 53 can inhibit the osteogenic transdifferentiation of VSMCs and the expression of COL1α1 by inhibiting the activation of the endoplasmic reticulum stress pathway PERK-eIF2α-ATF4, and finally delay the progress of VC and VF.

The present invention also provides a drug for inhibiting vascular calcification or a drug for inhibiting vascular fibrosis, and the drug uses the small molecular compound PMX 53 as the main active ingredient.

Preferably, pharmaceutically acceptable auxiliary materials are also included. The auxiliary materials are diluents, adhesives, lubricants, disintegrants, cosolvents, stabilizers, etc. and some pharmaceutical bases that can be used in the pharmaceutical field; they can also be functional pharmaceutical auxiliary materials available in the pharmaceutical field, including Surfactants, suspending agents, emulsifiers, and some new pharmaceutical polymer materials, such as cyclodextrin, chitosan, polylactic acid (PLA), polyglycolic acid polylactic acid copolymer (PLGA), hyaluronic acid, etc.

Preferably, the dosage form of the drug includes injection, injection powder, tablet, granule, capsule, drop pill, sustained-release preparation, and oral liquid preparation. PMX 53 is a known small molecule drug, soluble in phosphate buffered saline (PBS) or dimethyl sulfoxide, with good thermal stability, low cytotoxicity, good drug safety, and good pharmacokinetic properties. It can be flexibly administered in various ways such as oral, subcutaneous injection, intramuscular injection and intravenous injection.

The above-mentioned dosage form refers to the dosage form commonly used in clinical practice. The pharmaceutical preparation can be administered orally or parenterally (such as intravenously, subcutaneously, intraperitoneally or locally). If some drugs are unstable under gastric conditions, they can be given It is prepared as an enteric-coated tablet.

Compared with prior art, the beneficial effect of the present invention is:

VC and VF are common clinical vascular pathological changes, which can lead to high morbidity and mortality of cardiovascular diseases. However, there is still a lack of effective and cheap clinical drugs. To this end, the present invention provides a new application direction of the small molecule compound PMX 53, which can significantly inhibit the osteogenic transdifferentiation of VSMCs and the expression of COL1α1, thereby delaying the progress of VC and VF. Moreover, the mechanism of PMX 53 regulating VC and VF is related to its inhibition of the activation of the endoplasmic reticulum stress PERK-eIF2α-ATF4 signaling pathway. By inhibiting the activation of the above signaling pathway, it can inhibit the osteogenic transdifferentiation of VSMCs and the expression of COL1α1, and finally delay Progression of VC and VF. Therefore, PMX 53 is expected to be a candidate drug for anti-VC and VF, providing efficient and cheap small molecule compounds for anti-VC and VF, and providing new ideas and targets for the treatment of VC and VF.

Description of drawings

Figure 1 shows the upregulation of C5aR1 expression during VC and VF [(A) Von Kossa staining of human radial artery sections with or without VC and VF, immunohistochemical staining of COL1α1 and C5aR1, scale bar, 100 μm; (B) control group and AP Von Kossa staining, immunohistochemical staining of COL1α1 and C5aR1 in vivo model aortic section of mice in the same group, scale bar, 200 μm; (CD) Western blot analysis (C) and quantification (D) in vivo model of mice in the control group and AP group Expression of C5aR1, COL1α1, and markers of osteogenic transdifferentiation (RUNX2) in arteries. (EG) Alizarin red staining and Western blot analysis results of VSMCs exposed to Pi (0, 2.2, 2.4, 2.6, 2.8, 3.0 mM) for 7 days (E), as well as COL1α1, C5aR1, osteogenic transdifferentiation markers (BMP2 , RUNX2) and contractile phenotype markers (SM22α, α-SMA) expression quantitative analysis results (FG, F, G from left to right are 0, 2.2, 2.4, 2.6, 2.8, 3.0mM Pi); ( H) C5aR1 mRNA expression level in VSMCs exposed to Pi (2.6mM) for 72h; all values are expressed as mean ± SEM, ^* P<0.05];

Figure 2 shows that PMX 53 inhibits the osteogenic phenotype transformation and COL1α1 expression of VSMCs [first pretreatment with 1.25, 2.5 and 5.0 μM PMX 53 for half an hour, and then 2.6mM Pi and 100ng/mL recombinant human complement C5a to incubate VSMCs for 7 days, Alizarin red staining and Western blot analysis (A), and quantitative analysis (BC, B, C from left to right are Control, Pi, Pi+100ng/mL C5a, Pi+100ng/mL C5a+1.25μM PMX 53, Pi+100ng/mL C5a+2.5μM PMX 53, Pi+100ng/mL C5a+5μM PMX 53) COL1α1, osteogenic transdifferentiation markers (BMP2, RUNX2) and contractile phenotype markers (SM22α, α- SMA) expression changes, all values are expressed as mean ± SEM, ^* P<0.05];

Fig. 3 shows that PMX 53 delays the process of VC and VF [wild-type mice were randomly divided into 4 groups, 15 animals in each group, the control group was fed with no added mouse maintenance feed, and the AP group was fed with high adenine ( 0.15%) and phosphorus (1.5%) mice maintained feed; meanwhile, the AP plus phosphate buffered saline (PBS) group was subcutaneously injected with PBS (1mL/Kg/day), and the AP plus PMX 53 group was subcutaneously injected with PMX 53 (1mg/kg/day). Kg/day), then the calcium content in the aortic blood vessel was evaluated by Sisu red staining (A), the type I collagen content in the aortic blood vessel was evaluated by Masson staining (B), Western blot (C) and quantitative analysis (D, D From left to right in the middle: Control, AP, AP+PBS, AP+PMX 53) COL1α1, osteogenic transdifferentiation markers (BMP2, RUNX2) and contractile phenotype markers (SM22α, α-SMA) in aortic vessels The expression changes of , all values are expressed as mean ± SEM, ^* P<0.05];

Figure 4 shows that PMX 53 reduces the osteogenic phenotype transition of VSMCs and the expression of COL1α1 by inhibiting the PERK-eIF2α-ATF4 signaling pathway [through Western blot and quantitative analysis of the mouse model aorta in vivo (AB, B from left to right are Control, AP, AP+PBS, AP+PMX 53) and the endoplasmic reticulum in the in vitro cell model VSMCs (CE, D, E from left to right are Control, Pi, Pi+C5a, Pi+C5a+PMX 53) Expression changes of stress-related markers (glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (BIP), and major sensors of endoplasmic reticulum stress (PERK, IRE1α, ATF6), all values are expressed as mean ± SEM, ^* P<0.05].

Detailed ways

Specific embodiments of the present invention will be further described below. It should be noted here that the descriptions of these embodiments are used to help understand the present invention, but are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not constitute a conflict with each other.

The experimental methods in the following examples, unless otherwise specified, are conventional methods, and the test materials used in the following examples, unless otherwise specified, can be purchased through conventional commercial channels.

Example 1 Anti-vascular calcification and vascular fibrosis research of the small molecule compound PMX 53

1. Materials and methods

1.1. Experimental materials

Primary human vascular smooth muscle cells were purchased from the American Type Culture Collection; 8-week-old C57BL/6J male wild-type mice (weight 20-25g) were purchased from the Experimental Animal Center of Sun Yat-sen University. The mice were maintained on diet and added high adenine High-phosphorus maintenance diets for mice were purchased from Wuhan Yutaihe Technology Co., Ltd.; PMX 53 (molecular formula: C ₄₇ H ₆₅ N ₁₁ O ₇ ) was purchased from RD; inorganic phosphorus was purchased from Sigma; recombinant human complement C5a was purchased from RD .

1.2. Experimental method:

1.2.1, cell culture and in vitro cell model

Primary human aortic smooth muscle cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C in a 5% carbon dioxide incubator. In order to induce calcification and fibrosis models in vitro, VSMCs counted about 1×10 ⁶ per well were planted in a six-well plate, and the medium was changed after 24 hours, and inorganic phosphorus (Pi) was added, with a final concentration of Pi of 2.6 mM, and incubated For 7 days, medium and Pi were changed every 2 days.

1.2.2. In vivo mouse model and tissue collection

It has been confirmed that there are two lesions of VC and VF in the high adenine and high phosphorus (AP) mouse model, so this example carries out follow-up experiments through the same modeling, that is, feeding a high adenine and high phosphorus diet to construct a mouse model in vivo , to detect the effect of PMX 53 on two diseases of VC and VF. The wild-type mice were randomly divided into 4 groups, 15 animals in each group, wherein the control group was fed with mouse maintenance feed without any addition, and the AP group was fed with high adenine (0.15%) and high phosphorus (1.5%) feed Mice were maintained on chow. At the same time, the AP plus PBS group was subcutaneously injected with PBS (1mL/Kg/day) while feeding, and the AP plus PMX 53 group was subcutaneously injected with PMX 53 (1mg/Kg/day) while feeding. After 12 weeks of feeding and subcutaneous injection modeling, mice were euthanized to obtain aortic tissue.

1.2.3. Effect of PMX 53 on VCMCs osteogenic transdifferentiation and expression of COL1α1

The primary human aortic smooth muscle cells were seeded in a 6-well plate at a density of 1×10 ⁶ per well, and 2 mL of DMEM complete medium was added to each well, and 1.25, 2.5 and 5.0 μM PMX 53 were pretreated for half an hour after 24 hours, respectively. Then 2 mL of complete medium, Pi (final concentration 2.6 mM) and 100 ng/mL recombinant human complement C5a were added. PMX 53, medium, Pi, and recombinant human complement C5a were replaced every 2 days. After 7 days, the total protein of the cells was extracted by RIPA for Western Blot analysis, or the calcium content of the cells was evaluated by Alizarin staining.

2. Experimental results

2.1. The expression of C5aR1 is up-regulated during VC and VF

C5aR1 is expressed in VSMCs, macrophages, endothelial cells, etc. In order to observe the expression changes of C5aR1 (receptor 1 of complement protein C5a) during VC and VF, the human radial artery and mouse aorta were evaluated by Von Kossa staining. Calcium content, the expression of COL1α1 and C5aR1 in human radial artery and mouse aorta were detected by immunohistochemical method, the calcium content in VSMCs was evaluated by Sisu red staining, and the aorta of mouse in vivo model and VSMCs in vitro model were detected by Western Blot C5aR1 expression, RT-PCR method to detect the expression changes of C5aR1 mRNA in VSMCs in vitro model.

It was found that radial arteries with VC and VF exhibited higher expression of C5aR1 compared with radial arteries without VC and VF (Fig. 1A). Consistent with clinical observations in human radial arteries, C5aR1 levels were higher in mouse VC and VF aortas than controls, and COL1α1 expression was significantly increased in mouse VF aortic vessels (Fig. 1B–D). In addition, an in vitro model of VSMCs was constructed, and Alizarin red staining proved that Pi dose-dependently induced calcium deposition in VSMCs. In Western Blot analysis, it was observed that Pi dose-dependently promoted osteogenic transdifferentiation of VSMCs, which was manifested by increased expression of osteogenic phenotype markers (BMP2, RUNX2) and decreased expression of contractile phenotype markers (SM22α, α- SMA), and Pi dose-dependently increased the expression of COL1α1. Moreover, when the Pi concentration is 2.6mM, it has statistical significance, and subsequent experiments use 2.6mM for modeling. More importantly, Pi dose-dependently increased the protein expression level of C5aR1 during osteogenic transdifferentiation of VSMCs (Fig. 1E-G). And the C5aR1 mRNA level in VSMCs in vitro cell model was significantly higher than that in the control group (Fig. 1H). These data above indicate that C5aR1 is upregulated during VC and VF in vivo and in vitro.

2.2. PMX 53 inhibited VSMCs osteogenic phenotype transition and expression of COL1α1

In order to explore the effect of PMX 53 on VSMCs osteogenic phenotype transformation and COL1α1 expression, in the in vitro cell model, 1.25, 2.5 and 5.0μM PMX 53 were pretreated for half an hour, and then 2.6mM Pi and 100ng/mL recombinant human Complement C5a, calcium content was evaluated by Sithu red staining, and Western Blot was used to detect the expression levels of markers related to osteogenic transdifferentiation (RUNX2, BMP2) and contractile phenotype (SM22α, α-SMA), and COL1α1.

Sithol staining suggested that PMX 53 dose-dependently reduced calcium deposition in VSMCs. Western blot analysis showed that 5.0 μM PMX 53 significantly inhibited the increase in the expression of osteogenic transdifferentiation markers (RUNX2, BMP2), while the expression of contractile markers (SM22α, α-SMA) was reversed, and the expression level of COL1α1 was significantly reduced . It was shown that PMX53 inhibited the osteogenic transdifferentiation of VSMCs and the expression of COL1α1 (Fig. 2A-C).

2.3. PMX 53 delays the process of VC and VF

In order to further explore the effect of PMX 53 on VC and VF, the in vivo mouse model was constructed, and PMX53 or PBS was injected subcutaneously. After the model was established, the mouse aorta was obtained, and the calcium content in the aortic blood vessel was evaluated by Sisu red staining. Masson staining was used to evaluate the content of type I collagen in aortic blood vessels, and Western blot was used to detect the changes in the markers of osteogenic and contractile phenotypes and the expression level of COL1α1 in aortic blood vessels.

Staining of the whole vessel with mizurite indicated that compared with the AP+PBS group, the calcium deposition in the aortic vessels of the AP+PMX 53 group was significantly reduced (Fig. 3A). Masson staining indicated that compared with the AP+PBS group, the content of type I collagen in the aortic vessels of the AP+PMX 53 group was significantly reduced. Western blot analysis showed that compared with the AP+PBS group, PMX 53 decreased the expression of RUNX2, BMP2 and COL1α1 in the aorta of calcified mice, while the expression of contraction markers (SM22α, α-SMA) increased (Fig. 3B-C). Data show that PMX 53 can delay the progress of VC and VF.

2.4. PMX 53 reduces the osteogenic phenotype transdifferentiation and COL1α1 expression of VSMCs by inhibiting the activation of PERK-eIF2α-ATF4 signaling pathway

Because VC and VF are highly regulated by endoplasmic reticulum stress (there are three endoplasmic reticulum stress pathways: PERK-eIF2α-ATF4, IRE1α-XBP1 and ATF6). To this end, we next investigated whether PMX 53 delays VC and VF by regulating ER stress. The endoplasmic reticulum stress-related markers (glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP94) ) and the main sensor of endoplasmic reticulum stress (PERK , IRE1α, ATF6) expression changes.

The results suggested that VC and VF processes induced stress activation of the ER, manifested by increased levels of ER stress markers (GRP94 and BIP) in vivo and in vitro (Fig. 4A-E). Interestingly, C5a-C5aR1 significantly increased the levels of pPERK, but not pIRE1α and ATF6, and increased the levels of peIF-2α and ATF4, the downstream factors of the PERK signaling pathway. At the same time, the expressions of GRP94 and BIP were significantly reduced after PMX 53 pretreatment, suggesting that PMX 53 inhibited the stress activation of the endoplasmic reticulum. And PMX 53 further inhibited the activation of ER stress PERK-eIF2α-ATF4 signaling pathway (Fig. 4A-E). It was shown that PMX 53 could reduce the osteogenic phenotype transdifferentiation of VSMCs and the expression of COL1α1 by inhibiting the activation of PERK-eIF2α-ATF4 signaling pathway.

In summary, as a specific antagonist of C5aR1, the small molecule compound PMX 53 can competitively bind to C5aR1 on the surface of VSMCs with high affinity, and then inhibit the formation of VSMCs by inhibiting the activation of the endoplasmic reticulum stress pathway PERK-eIF2α-ATF4. Bone transdifferentiation and expression of COL1α1, ultimately delaying the progression of VC and VF, are promising drug candidates against VC and VF.

The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, without departing from the principle and spirit of the present invention, various changes, modifications, substitutions and modifications to these embodiments still fall within the protection scope of the present invention.

Claims (9)

1. Use of a small molecule compound PMX53 for the preparation of a medicament for inhibiting vascular calcification and/or vascular fibrosis.

2. Use according to claim 1, characterized in that vascular calcification and/or vascular fibrosis is caused by high adenine hyperphosphorylation.

3. The use according to claim 1, wherein the inhibition of vascular calcification is inhibition or reduction of vascular smooth muscle cell osteogenic phenotype transdifferentiation.

4. The use according to claim 1, wherein said inhibition of vascular fibrosis inhibits or reduces the expression of type I collagen α1.

5. The use according to claim 3, wherein said inhibiting or reducing vascular smooth muscle cell osteoblastic phenotype transdifferentiation is achieved by inhibiting activation of the PERK-eif2α -ATF4 signaling pathway.

6. The use according to claim 4, wherein said inhibition or reduction of the expression of type I collagen α1 is achieved by inhibiting the activation of the PERK-eif2α -ATF4 signaling pathway.

7. A medicament for inhibiting vascular calcification or a medicament for inhibiting vascular fibrosis, which is characterized in that the medicament takes a small molecular compound PMX53 as a main active ingredient.

8. The agent for inhibiting vascular calcification or inhibiting vascular fibrosis of claim 7, further comprising a pharmaceutically acceptable excipient.

9. The drug for inhibiting vascular calcification or drug for inhibiting vascular fibrosis according to claim 7, wherein the dosage forms of the drug include injection, injection powder, tablet, granule, capsule, dripping pill, sustained release preparation and oral liquid preparation.

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