High glucose promotes atherosclerosis by regulating miRNA let7d‐5p level

• Published in: Journal of diabetes investigation Vol. 15; no. 6; pp. 711 - 724
• Main Authors: Wang, Hua, Liu, Fentao, Zhao, Wenyu, Guo, Yiting, Mai, Peipei, Zhao, Songfeng, Wen, Zhiguo, Su, Jie, Li, Xuan, Wang, Yunlong, Zhang, Yanfang
• Format: Journal Article
• Language: English
• Published: Japan John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc; Wiley
• Subjects: Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Blood vessels; Cell Movement; Cell Proliferation; Cells, Cultured; Diabetes; Diabetes mellitus; Female; Genotype & phenotype; Glucose; Glucose - metabolism; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; High mobility group proteins; HMGA2 Protein - genetics; HMGA2 Protein - metabolism; Humans; Hyperglycemia; Male; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; MiRNA let7d‐5p; mRNA; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Original; Signal Transduction; Smooth muscle; Type 2 diabetes mellitus; β-Catenin; United States > US; China; Japan; Germany; MiRNA let7d‐5p; Atherosclerosis; Type 2 diabetes mellitus
• ISSN: 2040-1116; 2040-1124; 2040-1124
• DOI: 10.1111/jdi.14180

ABSTRACT Background MiRNA let7d‐5p has been recently reported to be abnormally expressed in diabetes‐associated atherosclerosis (AS). However, it still remains unknown how let7d‐5p contributes to the process of atherosclerosis. Methods Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d‐5p was assessed using quantitative RT‐PCR (qRT‐PCR). A series of in vitro experiments was used to determine the roles of let7d‐5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). Results We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d‐5p. In VSMCs, the expression of miRNA let7d‐5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d‐5p, whereas the opposite was true when let7d‐5p was inhibited, according to gain and loss of function studies. Mechanically, let7d‐5p might activate the GSK3β/β‐catenin signaling pathway via binding to the high mobility group AT‐Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP‐1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d‐5p levels. Conclusions High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d‐5p/HMGA2/GSK3β/β‐catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d‐5p. In this study, we reported that the miR let7d‐5p expression was decreased in the carotid plaque of patients with diabetes. We first revealed high glucose promoted the proliferation and migration of VSMCs by regulating the let7d‐5p/HMGA2/GSK3β/β‐catenin pathway, and liraglutide may alleviate atherosclerosis via up‐regulating miR let7d‐5p levels. GLP‐1RA liraglutide could inhibit the proliferation and migration of VSMCs by up‐regulating the level of let7d‐5p.