lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy,leading to atherogenesis  

作　　者：Yuhua Fan Yue Zhang Hongrui Zhao Wenfeng Liu Wanqing Xu Lintong Jiang Ranchen Xu Yue Zheng Xueqing Tang Xiaohan Li Limin Zhao Xin Liu Yang Hong Yuan Lin Hui Chen Yong Zhang 

机构地区：[1]Department of Pharmacology,State–Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Medicine Research,Ministry of Education,College of Pharmacy,Harbin Medical University,Harbin 150081,China [2]Department of Pathology and Pathophysiology,College of Basic Medical Sciences,Harbin Medical University-Daqing,Daqing 163319,China [3]Center for Drug Research and Development,Guangdong Pharmaceutical University,Guangzhou 510006,China

出　　处：《Frontiers of Medicine》2023年第2期317-329,共13页医学前沿（英文版）

基　　金：supported,in part,by the National Natural Science Foundation of China(Nos.81773735,81973313,and 81503069);the National Key R&D Program of China(No.2017YFC1702003);the Natural Science Foundation of Heilongjiang Province(No.ZD2022H002);the Fundamental Research Funds for the Provincial Universities-Academician Mr.Yu Weihan Foundation for Distinguished Young Scholars(No.JFYWH202001).

摘　　要：Long noncoding RNAs(lncRNAs)play a critical role in the regulation of atherosclerosis.Here,we investigated the role of the lncRNA growth arrest-specific 5(lncR-GAS5)in atherogenesis.We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis,which presented as increased plaque size and reduced collagen content.Moreover,impaired autophagy was observed,as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells.By contrast,lncR-GAS5 knockdown promoted autophagy.Moreover,serine/arginine-rich splicing factor 10(SRSF10)knockdown increased the LC3II/LC3I ratio and decreased the P62 level,thus enhancing the formation of autophagic vacuoles,autolysosomes,and autophagosomes.Mechanistically,lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium,which was reversed by the knockdown of SRSF10.Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene,SRSF10.Notably,miR-193-5p overexpression decreased plaque size and increased collagen content.Altogether,these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy.In conclusion,lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway.Thus,miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

关 键 词：lncR-GAS5 miR-193-5p splicing factor SRSF10 AUTOPHAGY ATHEROGENESIS 

分 类 号：R541.4[医药卫生—心血管疾病]