MEK1/2 inhibitor inhibits neointima formation by activating miR-126-3p/ C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) axis

Bioengineered

Jialing Ma¹  Yuanli Chen¹  Shuang Zhang¹  Yajun Duan¹  Xiaoyu He¹  Jihong Han¹  Xiaoxiao Yang¹  Yali Yan¹  Hongmei Xu¹  Mengmeng Zhu¹  Meixiu Jiang² 

[1] Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China;The Institute of Translational Medicine, the National Engineering Research Center for Bioengineering Drugs and the Technologies, Nanchang University, Nanchang, Jiangxi, China;

关键词: Neointima formation;    ERK1/2;    miR-126-3p;    RGS16;    endothelium repair;   

DOI  :  10.1080/21655979.2022.2063496

来源: DOAJ

【 摘 要 】

Endothelial dysfunction is an initial and essential step in vascular-remodeling diseases, including atherosclerosis and neointima formation. During vascular remodeling, activated endothelial cells can release pro-inflammatory factors that promote phenotypic switching of vascular smooth muscle cells (VSMCs) to the proliferative phenotype. We previously reported that MEK1/2 inhibitor, U0126, has a protective effect on the development of atherosclerosis and vascular calcification. However, the effect of MEK1/2 inhibitors on neointimal formation and the underlying mechanism is not fully understood. We determined that MEK1/2 inhibitor reduced carotid artery ligation-induced neointimal formation, while increased collagen and elastin levels and vascular integrality. Mechanistically, MEK1/2 inhibitor or ERK1/2 siRNA increased miR-126-3p level in endothelial cells, thereby inhibiting expression of regular of G-protein signaling 16 (RGS16), a miR-126-3p target gene, to activate the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signaling pathway. Accordingly, miR-126-3p was also increased by U0126 in serum and carotid artery. RGS16 was inhibited while CXCR4 and CXCL12 was increased by U0126 in neointimal areas, especially in the endothelium. Moreover, similar results were observed in atherosclerotic plaques of high-fat diet-fed apolipoprotein E deficiency (apoE−/−) mice. In addition, vascular cell adhesion molecule 1 (VCAM-1), another miR-126-3p target gene, was reduced by U0126 in the neointimal areas, resulting reduced monocytes/macrophages accumulation. Taken together, our results indicate that MEK1/2 inhibitor can reduce neointima formation by activating endothelial miR-126-3p production to facilitate endothelium repair while reduce monocyte adhesion/infiltration.

【 授权许可】

Unknown