Application of raltegravir in preparation of medicine for preventing and / or treating vascular remodeling diseases

Abstract

The invention provides application of raltegravir in preparation of a medicine for preventing and / or treating vascular remodeling diseases. A series of in-vitro cell experiments find that the Rategravir can influence activation of a Hippo / YAP pathway by inhibiting polymerization from gamma-actin to F-actin, further inhibit abnormal proliferation and migration ability of pulmonary artery smooth muscle cells (PASMCs) and inhibit conversion of the PASMCs from a contraction type to a synthetic type, so that pulmonary vascular remodeling is improved, and the pulmonary vascular remodeling effect is improved. The pulmonary vascular remodeling is expected to be fundamentally inhibited or reversed, and the prevention and treatment effects on pulmonary arterial hypertension are improved. Furthermore, the treatment effect of the Rattegravir in vivo is verified through a pulmonary arterial hypertension animal model. In a word, the invention discovers that the Rattegravir can achieve the purpose of preventing and treating pulmonary arterial hypertension from the pathogenesis level, and has a good application prospect and a higher clinical application value.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically, to the use of retegvir in the preparation of medicaments for the prevention and / or treatment of vascular remodeling diseases. Background Technology

[0002] Vascular remodeling diseases refer to a group of diseases with vascular remodeling (pathological changes in the cellular composition, structure, and function of the blood vessel wall) as the core pathological basis, which ultimately leads to abnormal blood vessel diameter, decreased elasticity, and impaired lumen patency, thereby causing organ ischemia or dysfunction. These include hypertension, pulmonary hypertension, restenosis after arteriosclerosis, and atherosclerosis.

[0003] Pulmonary hypertension (PH) is a malignant pulmonary vascular syndrome characterized by progressively increasing pulmonary vascular resistance and pulmonary artery pressure, ultimately leading to right heart failure and even death. Although the exact mechanisms of PH are not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are believed to promote its occurrence and progression. Epidemiological surveys show that there are over 75 million PH patients worldwide, with 80% located in developing countries. The prevalence is as high as 10% in people over 65 years of age, far exceeding the 1% prevalence in the general population. The median survival of untreated PH patients is only 2.8 years.

[0004] Currently, commonly used drugs for pulmonary hypertension (PH) include prostacyclin analogs or receptor agonists (such as treprostinil), endothelin receptor antagonists (such as macitentan), phosphodiesterase type 5 inhibitors (such as sildenafil), and soluble guanylate cyclase agonists (such as riociguat). However, these drugs are mainly used to dilate pulmonary vessels and relieve clinical symptoms in patients with pulmonary hypertension. Long-term use leads to drug resistance, and they cannot fundamentally inhibit or reverse pathological vascular remodeling. Therefore, even with the use of these drugs, the 5-year survival rate only increases to 57%. Therefore, finding new drugs that can reverse pulmonary vascular remodeling is of paramount importance for the clinical prevention and treatment of pulmonary hypertension.

[0005] Raltegravir is an antiretroviral drug, belonging to the HIV integrase strand transfer inhibitor (INSTI) class, primarily used to treat human immunodeficiency virus type 1 (HIV-1) infection. A review of domestic and international literature has not revealed any reports of its application in the prevention and treatment of pulmonary hypertension. Summary of the Invention

[0006] This invention addresses the lack of existing drugs that directly inhibit or reverse pulmonary vascular remodeling by providing a new use for ritegvir—its application in the preparation of drugs for the prevention and / or treatment of vascular remodeling diseases. Experimental verification shows that ritegvir can reduce the proliferation and migration of smooth muscle cells and inhibit the conversion of cells from contractile to synthetic types, thereby reversing pulmonary vascular remodeling, a key pathological change in the development of pulmonary vascular remodeling, and improving the prevention and treatment of pulmonary vascular remodeling. It has good application prospects and high clinical application value.

[0007] Based on the above, the present invention provides the use of retegvir in the preparation of medicaments for the prevention and / or treatment of vascular remodeling diseases.

[0008] Optionally, the chemical structural formula of the retegwein is shown in formula (I) below:

[0009]

[0010] Optionally, the vascular remodeling disease includes any one of hypertension, pulmonary hypertension, restenosis after arteriosclerosis, and atherosclerosis.

[0011] Optionally, the retegvir inhibits the polymerization of γ-actin to F-actin, thereby affecting the activation of the Hippo / YAP pathway and inhibiting the abnormal proliferation, migration, and phenotypic transformation of vascular smooth muscle cells, thus achieving the purpose of preventing and / or treating vascular remodeling diseases.

[0012] Optionally, the drug may be used alone or in the form of a pharmaceutical composition.

[0013] Optionally, the drug may also include a pharmaceutically acceptable carrier.

[0014] Optionally, the dosage form of the drug includes solid dosage form and liquid dosage form.

[0015] Optionally, the solid dosage form includes any one or more combinations of tablets, capsules, granules, pills, suppositories, films, gels, ointments, or powders.

[0016] Optionally, the liquid dosage form includes any one or more combinations of injections, mixtures, oral solutions, syrups, tinctures, sols, and emulsions.

[0017] Optionally, the effective concentration of retegvir is 160 mg / kg.

[0018] Compared with the prior art, the beneficial effects of the present invention include at least the following:

[0019] This invention is the first to discover that retegvir can affect the activation of the Hippo / YAP pathway by inhibiting the polymerization of γ-actin to F-actin, thereby inhibiting the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and inhibiting the conversion of PASMCs from contractile to synthetic types, thus improving pulmonary vascular remodeling. It can achieve the purpose of preventing and treating pulmonary hypertension from the pathogenesis level, and has good application prospects and high clinical application value. Attached Figure Description

[0020] Figure 1 The results of the EdU experiment in Example 1, which detected cell proliferation, are as follows:

[0021] A represents images taken using a fluorescence microscope; B represents the statistical values ​​of A.

[0022] Figure 2 The results of the cell scratch experiment in Example 1 are as follows:

[0023] A represents a photograph taken during the scratch test; B represents the statistical values ​​of A.

[0024] Figure 3 The results show the expression levels of contraction-related genes and synthesis-related genes in PASMCs detected by qPCR in Example 1.

[0025] Figure 4 This is the result of the investigation into the mechanism by which retegvir inhibits the hypoxia-induced contractile-to-synthetic phenotype conversion of PASMCs in Example 1; wherein:

[0026] A shows the immunofluorescence staining of F-actin and YAP in PASMCs cells;

[0027] BC is used for WB detection of p-YAP S127 Electrophoretic banding and numerical statistics of protein levels.

[0028] Figure 5 The results of hemodynamic testing in each group of mice in Example 2 are as follows:

[0029] A is a representative graph of right ventricular systolic pressure (RVSP);

[0030] B is a statistical chart of right ventricular systolic pressure (RVSP);

[0031] C is a statistical graph of the right ventricular hypertrophy index (RV / LV+S).

[0032] Figure 6 The results of HE staining of lung vessels in mice in each group in Example 2 are shown; where:

[0033] A is an HE-stained image; B and C are numerical statistics of A.

[0034] Figure 7 The results of hemodynamic testing in each group of mice in Example 3 are as follows:

[0035] A is a representative graph of right ventricular systolic pressure (RVSP);

[0036] B is a statistical chart of right ventricular systolic pressure (RVSP);

[0037] C is a statistical graph of the right ventricular hypertrophy index (RV / LV+S).

[0038] Figure 8 The results of HE staining of lung vessels in mice in each group in Example 3 are shown; where:

[0039] A is an HE-stained image; B and C are numerical statistics of A. Detailed Implementation

[0040] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0041] Vascular remodeling refers to structural or functional changes in blood vessels under physiological or pathological stimulation, involving changes such as thickening of the vessel wall, narrowing of the lumen, and decreased elasticity. It is an important pathological basis for cardiovascular diseases such as hypertension, pulmonary hypertension, restenosis after arteriosclerosis, and atherosclerosis.

[0042] Current medications for pulmonary hypertension primarily act on pulmonary vasodilation, failing to fundamentally inhibit or reverse pathological pulmonary vascular remodeling, resulting in a 5-year survival rate of less than 57%. Therefore, there is an urgent need to find novel drugs capable of reversing pulmonary vascular remodeling to improve treatment outcomes and survival rates for patients with pulmonary hypertension.

[0043] To achieve the above objectives, this invention, through extensive experiments and verification, ultimately discovered that retegvir can inhibit the activation of the Hippo / YAP pathway by inhibiting the polymerization of γ-actin into F-actin, thereby inhibiting the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and simultaneously inhibiting the conversion of PASMCs from contractile to synthetic types, thus inhibiting vascular remodeling and achieving the goal of preventing and treating pulmonary hypertension from the pathogenesis level.

[0044] Based on the above, the present invention provides the use of retegvir in the preparation of medicaments for the prevention and / or treatment of vascular remodeling diseases. The chemical structural formula of retegvir is shown in formula (I) below:

[0045]

[0046] In some embodiments, the vascular remodeling disease includes any one of hypertension, pulmonary hypertension, restenosis after arteriosclerosis, and atherosclerosis.

[0047] In some embodiments, the drug is used alone; in other embodiments, the drug is used in the form of a pharmaceutical composition.

[0048] In some embodiments, the drug also includes a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to a carrier used for the administration of a therapeutic agent, including various excipients and diluents. This term refers to pharmaceutical carriers that are not essential active ingredients themselves and do not cause excessive toxicity after administration. Suitable pharmaceutically acceptable carriers are well known to those skilled in the art. A thorough description of pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences. Pharmaceutically acceptable carriers in a composition may contain liquids such as water, phosphate buffer, Ringer's solution, physiological saline, balanced salt solution, glycerol, or sorbitol. Additionally, these carriers may contain auxiliary substances such as lubricants, flow aids, wetting agents or emulsifiers, pH buffers, and stabilizers such as albumin.

[0049] In some embodiments, the dosage form of the drug includes solid dosage forms and liquid dosage forms. The solid dosage forms include any one or more combinations of tablets, capsules, granules, pills, suppositories, films, gels, ointments, or powders. The liquid dosage forms include any one or more combinations of injections, mixtures, oral liquids, syrups, tinctures, sols, and emulsions.

[0050] The research process of the present invention will now be described in detail with reference to specific embodiments and accompanying drawings.

[0051] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in this invention all employ conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields. Unless otherwise specified, all materials and reagents used in this invention are commercially available. The Rettgwerk used in this embodiment was purchased from BioChemPartner, CAS No. 518048-05-0.

[0052] Example 1: Study on the inhibitory effect of retegvir on the proliferation and migration of PASMCs and on synthetic phenotypic conversion in vitro.

[0053] 1. EdU staining method for detecting cell proliferation

[0054] Log-growing PASMCs were seeded into 24-well plates, 1 × 10⁶ per well.5 Cells were cultured until they reached 60% confluence. The drug treatment group was given 10 μM retegvir (dissolved in DMSO solvent) under normoxic or hypooxic (1% oxygen concentration) conditions, while the control group was given the same volume of DMSO solvent under normoxic or hypooxic (1% oxygen concentration) conditions. The cells were then cultured for another 48 h.

[0055] After culture, the culture medium in each group was treated as follows: cells were incubated with 2×EdU solution for 2 hours, washed, fixed with 4% paraformaldehyde, and then perforated using Triton X-100. EdU click reaction solution was then added and reacted for 30 minutes. After washing, nuclei were stained with Hoechst 3342 for 10 minutes, washed again, and photographed. ImageJ was used to calculate the EdU ratio to assess cell proliferation.

[0056] The results are as follows Figure 1 As shown in Figures A and B, compared with the control group under normoxic conditions, the fluorescence value of the control group under hypoxic conditions was significantly increased, indicating that hypoxia significantly promoted the proliferation of PASMCs. However, after co-culturing with retegvir, the fluorescence value of the cell culture medium in the treatment group was significantly lower than that in the control group under hypoxia conditions. This shows that retegvir can significantly inhibit the abnormal proliferation of PASMCs induced by hypoxia.

[0057] 2. Scratch assay for cell migration

[0058] Log-growing PASMCs were seeded into 6-well plates, 1 × 10⁶ per well. 5 Cells were streaked vertically to the bottom of a plate using a 200 μL pipette tip when they reached 80% confluence. After washing twice with PBS, the cells were photographed. After photographing, serum-free medium with or without retegvir was added, and the cells were treated under normoxic or hypoxic (1% oxygen concentration) conditions for 12 h, followed by photographing again. ImageJ was used to calculate the scratch width to assess cell migration.

[0059] The results are as follows Figure 2 As shown in Figures A and B, compared to the control group under normoxic conditions, the scratch width of the control group under hypoxic conditions was significantly reduced, indicating that hypoxia promoted the migration ability of PASMCs. However, after co-culturing with retegvir, the scratch width of the treatment group was significantly greater than that of the control group under hypoxia, indicating that retegvir can inhibit hypoxia-induced migration of PASMCs.

[0060] 3. qPCR detection of cell proliferation and gene synthesis phenotypes

[0061] Log-growing PASMCs were seeded into 6-well plates, 1 × 10⁶ per well. 6Cells were cultured until they reached 60% confluence. The drug treatment group was given 10 μM retegvir (dissolved in DMSO solvent) under normoxic or hypooxic (1% oxygen concentration) conditions, while the control group was given the same volume of DMSO solvent under normoxic or hypooxic (1% oxygen concentration) conditions. The cells were then cultured for another 48 h.

[0062] After culture, the culture medium for each group was treated as follows: the medium was aspirated and washed twice with PBS; total RNA was extracted from PASMCs using TRIzol reagent (purchased from Accurate Biology), following the manufacturer's instructions; 1 μg of total RNA was reverse transcribed into cDNA using HiScript III All-in-One RT SuperMix (purchased from Vazyme, Cat#R333-01); quantitative real-time PCR was performed on a Bio-Rad CFX96 (USA). The thermal cycling conditions were set as follows: initial denaturation at 95°C for 1 min; followed by 40 cycles, each consisting of 95°C for 15 s and 60°C for 30 s. Melting curve analysis (65–95°C, stepwise heating, 5 s holding time per step) was performed after amplification to verify the specificity of the amplified products. Gene expression levels were normalized to the endogenous reference gene β-actin and calculated using the 2-ΔΔCt method.

[0063] The results are as follows Figure 3 As shown, comparing the experimental results of the two control groups reveals that hypoxia induced a phenotypic shift in PASMCs from contractile to anabolic morphology, leading to pulmonary vascular remodeling and deterioration. However, after co-culturing with retegvir, compared to the hypoxia control group, the contraction-related genes and anabolic genes in the hypoxia-treated PASMCs were significantly upregulated and significantly downregulated in the hypoxia-treated group. Specifically, MYH11 (contraction dynamin: encoding smooth muscle myosin heavy chain, involved in cell contraction and tension maintenance), TAGLN (contraction regulator: stabilizing the actin cytoskeleton, promoting smooth muscle cell differentiation and contractile function), ACTA2 (structural cytoskeleton protein: encoding α-smooth muscle actin, constituting the core component of the cell contraction apparatus), and CNN1 (calmodulin inhibitor: regulating actin-myosin interaction) were increased; CCND1 (cell cycle kinetic protein: promoting G1 / S phase transition, driving cell proliferation), COL1A1 (matrix structural protein: constituting type I collagen fibers, providing tissue mechanical support), TNC (damage response protein: temporarily expressed in tissue remodeling, promoting cell migration and proliferation), and FN1 (adhesion-migration regulator: mediating cell-matrix adhesion, supporting cell migration and tissue repair) were downregulated. These results suggest that Rettgvir inhibits the hypoxia-induced contractile-to-synthetic phenotype transition of PASMCs.

[0064] 4. Investigation into the mechanism by which Rettgvir inhibits the hypoxia-induced contractile-to-synthetic phenotype transition of PASMCs.

[0065] Studies have shown that the development and progression of PH involve the Hippo pathway or certain components thereof. The Hippo signaling pathway regulates cell differentiation, tissue homeostasis, and organ size by modulating cell survival, proliferation, and apoptosis. This pathway transmits extracellular signals into the cell, which, through a cascade of enzymatic reactions, are transmitted to the nucleus via Yes-associated protein (YAP), where they bind to transcription factors and influence the transcription of downstream genes. Phosphorylation of YAP (p-YAP) in the cytoplasm further contributes to this process. S127 This leads to the degradation of YAP, resulting in reduced YAP nuclear translocation and inhibition of downstream transcription.

[0066] To investigate the specific mechanism by which retegvir inhibits the hypoxia-induced contractile-to-synthetic phenotype conversion of PASMCs, the following experiments were conducted in this invention:

[0067] (1) Immunofluorescence staining of F-actin and YAP

[0068] Log-growing PASMCs were seeded into 6-well plates, 1 × 10⁶ per well. 6 Cells were cultured until they reached 60% confluence. The drug treatment group was given 10 μM retegvir (dissolved in DMSO solvent) under normoxic or hypooxic (1% oxygen concentration) conditions, while the control group was given the same volume of DMSO solvent under normoxic or hypooxic (1% oxygen concentration) conditions. The cells were then cultured for another 48 h.

[0069] After culture, the cells in each group were treated as follows: after removing the culture medium, the cells were washed with PBS, fixed with 4% paraformaldehyde, and then perforated with Triton X-100. After blocking with 3% BSA for 30 min, the cells were incubated with YAP primary antibody at 4°C overnight. After rinsing with PBS, the cells were incubated with phalloidin for 2 h. After washing with PBS, the cells were incubated with Alexa Fluor-bound secondary antibody (1:1000, Invitrogen) at room temperature for 1.5 h. Finally, DAPI staining and slide photography were performed.

[0070] The results are as follows Figure 4 As shown in Figure A, hypoxia induced increased F-actin polymerization and YAP nuclear translocation in PASMCs cells, but retegvir administration significantly inhibited these changes, resulting in decreased F-actin polymerization and YAP nuclear translocation. This indicates that YAP is phosphorylated more in the cytoplasm and subsequently used as p-YAP. S127 The degradation of YAP reduces nuclear translocation and inhibits the expression of downstream proliferating genes.

[0071] (2) WB detection of p-YAP S127 Protein content

[0072] Based on the above experimental results, further analysis was conducted on the p-YAP of each group of cells. S127 Protein levels were measured using the following method: Cells from each group were washed twice with PBS after the culture medium was removed; pre-chilled RIPA strong lysis buffer (with protease inhibitors added immediately before use) was added, and cells were scraped and collected into centrifuge tubes. After lysis on ice for 10 min, the supernatant was collected by centrifugation at 12000 rpm; after BCA quantification, loading buffer was added, and the cells were boiled at 100℃ for 10 min and then stored at -20℃. Proteins were separated using a 10% SDS-PAGE gel and transferred to a 0.45 μm PVDF membrane. After blocking with 5% skim milk at room temperature for 1.5 h, the membrane was incubated overnight with a specific primary antibody. The next day, the membrane was incubated with HRP-labeled secondary antibody at room temperature for 1.5 h, and then developed using an A1600 colorimetric system.

[0073] The results are as follows Figure 4 As shown in BC, retegvir administration caused p-YAP S127 The increased protein expression indicates that YAP is phosphorylated and acts as p-YAP. S127 Increased degradation leads to reduced YAP nuclear translocation, thereby inhibiting the expression of downstream proliferation genes.

[0074] These results indicate that retegvir can affect the activation of the Hippo / YAP pathway by inhibiting the polymerization of γ-actin to F-actin, thereby inhibiting the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and inhibiting the conversion of PASMCs from contractile to synthetic forms. This improves pulmonary vascular remodeling and is expected to fundamentally inhibit or reverse pulmonary vascular remodeling, thus improving the prevention and treatment of pulmonary hypertension.

[0075] Further animal experiments were conducted to verify the preventive and therapeutic effects of retegvir in pulmonary hypertension.

[0076] Example 2: Protective effect of retegvir on SuHx-induced PH vascular remodeling in mice.

[0077] Thirty 8-week-old male C57BL / 6 mice were randomly divided into four groups: normoxic group, normoxic drug administration group, hypoxia model group (SuHx) group, and hypoxia drug administration group (SuHx + ritigvir). The normoxic group and normoxic drug administration group did not undergo hypoxia induction modeling, while the hypoxia model group and hypoxia drug administration group underwent modeling treatment: mice were placed in a 10% oxygen concentration hypoxic chamber for four weeks, and SU5416 (20 mg / kg) was subcutaneously injected once a week to induce a mouse pulmonary hypertension model. The drug administration group received 160 mg / kg ritigvir by gavage daily starting two weeks after hypoxia modeling until the end of the experiment. After the experiment, the following tests were performed:

[0078] (1) Hemodynamic testing

[0079] Right ventricular pressure measurement: After anesthetizing mice with tribromoethanol, the chest wall was carefully cut open to expose the heart. The tip of a 1.2F miniature pressure sensor catheter was inserted into the right ventricle, and the right ventricular pressure value of the mice was stably and continuously measured using a PowerLab data acquisition system.

[0080] Cardiac function assessment: Lung tissue was irrigated with PBS from the right ventricle until it turned white. The mouse ventricle was carefully cut off, and the right ventricular (RV), left ventricular (LV), and interventricular septum (S) were separated, weighed, and recorded. The RV / (LV+S) value was calculated and statistically analyzed.

[0081] The results are as follows Figure 5 As shown in the AC, SuHx induction significantly increased the right ventricular systolic pressure and right ventricular hypertrophy index (RV / (LV+S)) in mice. However, after administration of retegvir, the right ventricular systolic pressure in mice was significantly reduced, indicating that their pulmonary artery pressure was lower than that in the model group. At the same time, the right ventricular hypertrophy index (RV / (LV+S)) decreased, indicating that the right ventricular hypertrophy caused by the increase in pulmonary artery pressure was also alleviated.

[0082] (2) HE pathological staining

[0083] Mouse lung tissue was fixed in 4% paraformaldehyde for 24 hours, then embedded in paraffin, sectioned, and stained with H&E.

[0084] The results are as follows Figure 6 As shown in the AC, SuHx induction significantly increased the degree of pulmonary artery vascular muscularization and vessel thickness in mice, but after administration of ritegvir, the degree of pulmonary artery vascular muscularization in mice was significantly reduced and the vessels became thinner, indicating that ritegvir can alleviate SuHx-induced thickening of the pulmonary artery wall in mice.

[0085] Example 3: Protective effect of ritegvir on MCT-induced vascular remodeling in rat PAH

[0086] Thirty 8-week-old male SD rats were randomly divided into three groups: a normoxic group, an MCT model group, and an MCT administration group (MCT + ritigvir). The MCT model group and the MCT administration group underwent modeling treatment: rats were anesthetized with 3% isoflurane gas and administered a single subcutaneous injection of monocrotaline (MCT) 60 mg / kg for four weeks to induce a rat pulmonary hypertension model. Two weeks after the MCT injection, the administration group received ritigvir 160 mg / kg daily by gavage until the end of the experiment. After the experiment, hemodynamic monitoring and HE pathological staining were performed; specific procedures are detailed in the relevant section of Example 2.

[0087] The results showed that, compared with the MCT model group, the right ventricular systolic pressure was reduced and the right ventricular hypertrophy index (RV / (LV+S)) was reduced in the MCT-treated rats. Figure 7 The AC (acute pulmonary artery pressure) indicated that the right ventricular thickening caused by increased pulmonary artery pressure was also alleviated. Furthermore, HE staining revealed a decrease in pulmonary artery vascular muscularization and thinning of the vessels. Figure 8 The results showed that retegvir could alleviate MCT-induced thickening of the pulmonary artery wall in rats.

[0088] In summary, this invention is the first to discover that retegvir can affect the activation of the Hippo / YAP pathway by inhibiting the polymerization of γ-actin to F-actin, thereby inhibiting the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and inhibiting the conversion of PASMCs from contractile to synthetic forms, thus improving pulmonary vascular remodeling. It can achieve the purpose of preventing and treating pulmonary hypertension from the pathogenesis level, and has good application prospects and high clinical application value.

[0089] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. Use of raltegravir in the preparation of a medicament for preventing and / or treating a vascular remodeling disease.

2. Use according to claim 1, wherein The chemical structure of the raltegravir is shown in the following formula (I):

3. The use according to claim 1, wherein The vascular remodeling disease includes any one of hypertension, pulmonary arterial hypertension, post-angioplasty restenosis, and atherosclerosis.

4. The use according to claim 1, wherein The raltegravir affects the activation of the Hippo / YAP pathway by inhibiting the polymerization of γ-actin to F-actin, thereby inhibiting the abnormal proliferation, migration and phenotype conversion of vascular smooth muscle cells, and achieving the purpose of preventing and / or treating the vascular remodeling disease.

5. The use according to claim 1, wherein The medicament is used alone or in the form of a pharmaceutical composition.

6. The use according to claim 1, wherein The medicament also includes a pharmaceutically acceptable carrier.

7. The use according to claim 1, wherein The dosage form of the medicament includes a solid dosage form and a liquid dosage form.

8. Use according to claim 7, wherein the compound is ###0002### The solid dosage form includes any one or a combination of tablets, capsules, granules, pills, suppositories, films, gums, pastes or powders.

9. The use according to claim 7, wherein the compound is ###0002### The liquid dosage form includes any one or a combination of injection solutions, mixtures, oral solutions, syrups, wine, sols, emulsions.

10. The use according to claim 1, wherein The concentration of the raltegravir is 160 mg / kg.

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