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Medicinal application of interfering with annexin a2 sulfhydryl nitrosylation modification

A technology of nitrosylation and mercapto, which is applied in the field of biomedicine, can solve problems that have not been studied and reported, and achieve the effect of important medicinal value

Active Publication Date: 2021-03-02
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the role and mechanism of sulfhydryl nitrosylation modification of ANXA2 in cardiovascular diseases have not yet been studied or reported.

Method used

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  • Medicinal application of interfering with annexin a2 sulfhydryl nitrosylation modification
  • Medicinal application of interfering with annexin a2 sulfhydryl nitrosylation modification
  • Medicinal application of interfering with annexin a2 sulfhydryl nitrosylation modification

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1 Research experiment on the correlation between sulfhydryl nitrosylation modification of ANXA2 protein and atherosclerosis-related vascular diseases

[0029] In order to explore the role of ANXA2 protein sulfhydryl nitrosylation modification in atherosclerosis-related vascular diseases, EA.hy926 endothelial cells were cultured (Xie L, et al. Br J Pharmacol.2012; 165(3):754-64. ), the experimental group was stimulated with oxLDL (oxidized low-density lipoprotein, 100 μg / mL) for 2 hours to cause endothelial cell injury, and the endothelial cell injury model was constructed. -switch detection (see the literature "Xie L, et al. Diabetes. 2016 Jun 22." for the detection method) the level of sulfhydryl nitrosylation modification (SNO-ANXA2) of ANXA2, the detection results are as follows figure 1 shown. figure 1 In A, SNO-ANXA2 represents the thiol nitrosylation content of ANXA2, Total-ANXA2 represents the total ANXA2 protein level, and β-actin represents the content...

Embodiment 2

[0033] Example 2 Screening experiment of ANXA2 protein sulfhydryl nitrosylation modification sites

[0034] In order to further clarify the role of ANXA2 protein sulfhydryl nitrosylation modification in atherosclerosis-related vascular diseases, this example combines liquid chromatography tandem mass spectrometry (LC-MS / MS) technology (Xie L, et al.Diabetes.2016 Jun22.), treated EA.hy926 endothelial cells with NO donor sodium nitroprusside (SNP) (100 μM), screened the sulfhydryl nitrosylation modification site of ANXA2, and found that EA.hy926 endothelial cells acted on by oxLDL In the ANXA2 cysteine ​​C133 site, a thiol nitrosylation modification occurred ( Figure 4 ).

[0035] The ANXA2 cysteine ​​Cys133 mutant alanine (C133A) was transfected with lip3000 transfection reagent to EA.hy926 cells, and it was further concluded that the C133 site of ANXA2 was modified by thiol nitrosylation ( Figure 5 ). Figure 5 In A, SNO-HA is exogenous SNO-ANXA2, Total-HA is the total pr...

Embodiment 3

[0039] Example 3 Application of thiol-nitrosylation modification of ANXA2 protein in the preparation of drugs for the prevention and treatment of atherosclerosis-related vascular diseases

[0040] In order to further verify the role of thiol-nitrosylation modification of ANXA2 protein in atherosclerosis-related vascular diseases, we injected adeno-associated virus 10 into the tail vein of 8-week-old mice. 11 A / only (Wang L, et al. Nature. 2016Dec7;540(7634):579-582.; Varadi K, et al. Gene Ther. 2012Aug; 19(8):800-9.), endothelial cells specifically overexpressed the 133-site mutation and wild-type ANXA2 protein, and fed the constructed mice with normal cholesterol (SPF grade) or high cholesterol diet (D12108C) 1 week after injection A model of atherosclerosis-related vascular disease. The adeno-associated virus used in this example is an endothelial-specific virus, donated by Professor Huang Yu of the Chinese University of Hong Kong, and its nucleotide sequence is shown in...

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Abstract

The invention provides an application of thiol and nitrosylation modification of intervention annexin A2 (ANXA2) to preparation of medicines for preventing and treating atherosclerosis related blood vessel diseases, and relates to the field of the cardiovascular system. The thiol and nitrosylation modification level of ANXA2 in blood vessel tissue of animals suffering from atherosclerosis is increased. At cell level, a Cys133 site of mutation ANXA2 can restrain increase of adhesive attachment of THP1 cells and endothelial cells caused by oxLDL, and reduce mRNA level of ICAM1 and VCAM1. At animal level, the Cys133 site of mutation ANXA2 can restrain increase of atherosclerotic plaque caused by high fat diet, reduce mRNA level of ICAM1 and VCAM1 and vascular endothelial dilatation functionsand improve the atherosclerosis related blood vessel diseases. According to the application of the invention, a new preparation method of medicines for preventing and treating the atherosclerosis related blood vessel diseases is developed, and meaningful reference is provided for preventing and treating the atherosclerosis related blood vessel diseases.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of the sulfhydryl nitrosylation modification of annexin A2 (Annexin A2, ANXA2) in the preparation of drugs for the prevention and treatment of atherosclerosis-related vascular diseases. Background technique [0002] With the rapid development of today's society, cardiovascular disease, as the first of the "three major killers" of human health, is gradually reducing the quality of human life and seriously threatening human life and health. Vascular endothelial dysfunction (VED) has become a key regulator of many cardiovascular diseases, such as atherosclerosis (AS). AS is a chronic inflammatory vascular disease related to dyslipidemia. The vascular endothelium plays an important physiological role as a permeability barrier for the exchange of substances inside and outside the blood vessel. AS is caused by multiple factors, and its pathogenesis is complex, which has not ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K35/761A61P9/10
CPCA61K35/761A61K45/00A61P9/10
Inventor 季勇郑乔李雪松谢利平
Owner NANJING MEDICAL UNIV
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