Application of MAT2A as anti-inflammatory target in treatment of atherosclerosis

Abstract

The invention discloses application of MAT2A as an anti-inflammatory target spot in treatment of atherosclerosis. Research finds that in carotid plaque of a symptomatic atherosclerotic patient and aortic sinus lesions of an ApoE- / -mouse with advanced atherosclerotic plaque, the accumulation of methionine adenosine transferase 2A (MAT2A) in CD68 + macrophages is increased, an MAT2A inhibitor FIDAS-5 can play an inhibition role by combining with an MAT2A active site, and the use of the MAT2A inhibitor FIDAS-5 can be used for inhibiting the aortic sinus lesions of the ApoE- / -mouse with advanced atherosclerotic plaque. Further, inflammatory response of atherosclerosis patients is relieved, and the process of atherosclerosis is delayed The invention provides a new therapeutic target and technical means for the treatment of atherosclerosis.

Description

Technical Field

[0001] The present invention relates to an anti - inflammatory target for treating atherosclerosis, and particularly to the application of MAT2A as an anti - inflammatory target in the treatment of atherosclerosis. The present invention belongs to the field of pharmaceutical technology. Background Art

[0002] Methionine is an essential amino acid in the human body, which is converted by methionine adenosyltransferase 2A (MAT2A) into the universal methylation donor S - adenosyl - methionine (SAM) in the body, and directly affects the body's methylation potential. Currently, studies have found that MAT2A is highly expressed in tissues such as liver cancer, colon cancer, gastric cancer, and non - small cell lung cancer, and specific inhibitors of MAT2A can be used for tumor treatment.

[0003] As a complex chronic inflammatory disease, atherosclerosis has become the main reason for the increasing annual cardiovascular mortality globally. The inflammatory response is a driving factor and sufficient condition for the progression of atherosclerosis and the formation of vulnerable plaques. Low - grade systemic inflammation can promote the continuous progression of atherosclerosis. Traditional anti - inflammatory treatment paradigms represented by canakinumab or low - dose colchicine can reduce the occurrence of adverse cardiovascular events in patients with atherosclerosis, but there are still residual risks and immune side effects that limit their clinical application. It is urgent to explore new targets to further optimize the anti - inflammatory treatment strategy for atherosclerosis.

[0004] The present invention aims to provide the application of MAT2A as an anti - inflammatory target in the treatment of atherosclerosis. Through immunofluorescence co - localization, it is found that MAT2A is up - regulated in macrophages of atherosclerotic plaques. Further, by intervening MAT2A with the MAT2A - specific inhibitor FIDAS - 5, it is found that it can delay the progression of atherosclerotic plaques by weakening the pro - inflammatory function of macrophages, that is, MAT2A can be used as a new molecular drug target for anti - inflammatory treatment of atherosclerosis. The proposal of the present invention provides a technical means for the prevention and treatment of atherosclerosis. Summary of the Invention

[0005] The object of the present invention is to provide the application of methionine adenosyltransferase 2A (MAT2A) as an anti - inflammatory target in the treatment of atherosclerosis.

[0006] To achieve the above object, the present invention adopts the following technical means:

[0007] The present invention first proposes the application of methionine adenosyltransferase 2A (MAT2A) as an anti - inflammatory target in the preparation of drugs for treating atherosclerosis. And

[0008] The application of an inhibitor of methionine adenosyltransferase 2A (MAT2A) in the preparation of drugs for treating atherosclerosis.

[0009] Among them, preferably, the inhibitor of methionine adenosyltransferase 2A (MAT2A) is (E)-4-(2-chloro-6-fluorostyryl)-N-methylaniline (abbreviated as FIDAS-5), with a CAS number of 1391934-98-7, a molecular weight of 261.72, and a molecular formula of C 15 H 13 ClFN.

[0010] Among them, preferably, the drug is an oral drug.

[0011] Among them, preferably, the drug can reduce the inflammatory response of patients with atherosclerosis and delay the progression of atherosclerosis.

[0012] Compared with the prior art, the beneficial effects of the present invention are:

[0013] The present invention provides the application of MAT2A as a drug target for the treatment of atherosclerosis. By inhibiting MAT2A, the inflammatory response of patients with atherosclerosis can be reduced, and the progression of atherosclerosis can be delayed. The present invention provides a new treatment target and technical means for the treatment of atherosclerosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 It is a diagram showing the expression results of MAT2A in atherosclerosis;

[0015] Among them, (A) Representative immunofluorescence images and quantification of MAT2A and CD68 in carotid artery plaques of symptomatic and asymptomatic atherosclerosis patients (n = 6, scale bar = 50 μm); (B) Aorta sinus atherosclerosis plaques of ApoE mice fed a high-fat diet for 10 weeks and 16 weeks - / - Representative immunofluorescence images and quantification of MAT2A and CD68 in atherosclerotic plaques (n = 6, scale bar = 100 μm);

[0016] Figure 2 It is a diagram showing that inhibiting MAT2A can reduce the formation of atherosclerotic plaques;

[0017] Among them, (A) Flow chart of the experimental process; (B) Representative photographs of atherosclerotic plaques in the aortic arch and its branch arteries; (C) Representative images and quantitative analysis of Oil Red O-stained whole aorta (n = 8; scale bar = 2 mm); (D) and (E) Representative images and quantitative analysis of Oil Red O-stained aortic root (n = 8; scale bar = 200 μm); (F) Representative images of H&E and Masson's trichrome staining of aortic root, scale bar = 200 μm; (G) Quantification of plaque area, percentage of necrotic core and collagen in aortic root (n = 8); (H) and (I) CD68 in atherosclerotic plaques in the aortic root of mice treated with FIDAS-5+ Immunohistochemistry and vulnerability index of macrophages, n = 8, scale bar = 100 μm;

[0018] Figure 3 Result graph showing that inhibiting MAT2A can attenuate inflammation in atherosclerotic mice;

[0019] Among them, (A) CD45 in bone marrow (n = 6) and peripheral blood (n = 6) + CD11b + CD115 + Ly6G - Ly6C hi Representative flow cytometry plots and quantitative analysis of monocytes; (B) Analysis of AIM2, CCL2, and MMP9 mRNA levels in peripheral blood monocytes by qRT-PCR (n = 6). Detailed implementation manners

[0020] To elaborate the above objects and features of the present invention in detail, the following will further illustrate the detailed implementation manners of the present invention with reference to the accompanying drawings of the specification, but the present invention is not limited to the following examples.

[0021] Example 1 MAT2A is highly expressed in both atherosclerotic patients and mice

[0022] In carotid artery plaques of symptomatic atherosclerotic patients ( Figure 1 A) and aortic sinus lesions of ApoE - / - mice with advanced atherosclerotic plaques ( Figure 1 B), we observed an increased accumulation of MAT2A in CD68 + macrophages.

[0023] Example 2 Effect of MAT2A-specific inhibitor FIDAS-5 on atherosclerotic progression in mice Method:

[0024] 1. Establish an atherosclerotic mouse model:

[0025] ApoE - / - mice were fed a high-fat diet (a high-fat diet containing 42.09% fat, 19.19% protein, and 38.72% carbohydrates) for 16 weeks to establish an atherosclerotic mouse model. All ApoE - / - mice were maintained under specific pathogen-free (SPF) conditions, and the breeding environment was maintained at a controllable constant temperature and a 12-hour light / dark cycle, denoted as the control group.

[0026] 2. Establish a MAT2A drug intervention model:

[0027] ApoE - / - mice aged 8 - 10 weeks were selected.Mice were fed a high-fat diet for 16 weeks. Starting from the 10th week of high-fat feeding, ApoE - / - mice were given FIDAS-5 (10 mg / kg) by gavage every other day until the end of the 16th week of high-fat diet feeding. Then the mice were euthanized( Figure 2 A). Aortic tissue, heart tissue, bone marrow, peripheral blood monocytes, etc. were taken for subsequent experiments, which was recorded as the FIDAS-5 group.

[0028] Results:

[0029] After administration of FIDAS-5, we observed that the atherosclerotic plaque areas in the whole aorta and aortic root of the mice were significantly reduced( Figure 2 B-E). In the aortic root lesions of MAT2A-inhibited ApoE - / - mice, the plaque area and the proportion of necrotic core were significantly reduced, while the collagen content increased( Figure 2 F-G). In addition, the number of CD68 + macrophages and the plaque vulnerability index were significantly reduced( Figure 2 H-I). In summary, the application of the MAT2A-specific inhibitor FIDAS-5 can delay the progression of atherosclerosis in mice.

[0030] Example 3 Effects of the MAT2A-specific inhibitor FIDAS-5 on inflammation in atherosclerotic mice. The methods for constructing atherosclerotic mouse models and MAT2A drug intervention models were the same as those in Example 2.

[0031] Bone marrow and peripheral blood of mice in the control group and the FIDAS-5 group were extracted for flow cytometry detection. The results showed that the number of Ly6C hi monocyte subsets in the bone marrow and peripheral blood of the FIDAS-5 group mice decreased( Figure 3 A), and the expression levels of AIM2, CCL2, and MMP9 decreased( Figure 3 B), indicating that the application of the MAT2A-specific inhibitor FIDAS-5 can reduce the inflammation in atherosclerotic mice.

Claims

1. Use of methionine adenosyltransferase 2A (MAT2A) as an anti-inflammatory target in the preparation of a medicament for treating atherosclerosis.

2. Use of an inhibitor of methionine adenosyltransferase 2A (MAT2A) in the preparation of a medicament for treating atherosclerosis.

3. The application according to claim 2, characterized in that, The inhibitor of methionine adenosyltransferase 2A (MAT2A) is (E)-4-(2-chloro-6-fluorostyryl)-N-methylaniline (FIDAS-5).

4. The application according to claim 2, wherein The medicament is an oral medicament.

5. The application according to claim 2, characterized in that The medicament can reduce the inflammatory response of patients with atherosclerosis and delay the progression of atherosclerosis.

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