Commutative regulation between endothelial NO synthase and insulin receptor substrate 2 by microRNAs  

作　　者：Xiaoli Sun Huizhen Lv Peng Zhao Jinlong He Qinghua Cui Minxin Wei Shiqing Feng Yi Zhu 

机构地区：[1]Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China [2]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA [3]Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University,Tianjin Key Laboratory of Metabolic Diseases, Tianjin 300070, China [4]Department of Cardiac Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China [5]Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, China

出　　处：《Journal of Molecular Cell Biology》2019年第6期509-520,共12页分子细胞生物学报（英文版）

基　　金：the Ministry of Science and Technology of China (2016YFC0903000);the National Natural Science Foundation of China (81420108003 and 81730014);the Tianjin Municipal Science and Technology Project (14JCYBJC41800).

摘　　要：Endothelial NO synthase (eNOS) expression is regulated by a number of transcriptional and post-transcriptional mechanisms, but the effects of competing endogenous RNAs (ceRNAs) on eNOS mRNA and the underlying mechanisms are still unknown. Our bioinformatic analysis revealed three highly expressed eNOS-targeting miRNAs (miR-15b, miR-16, and miR-30b) in human endothelial cells (ECs). Among the 1103 mRNA targets of these three miRNAs, 15 mRNAs share a common disease association with eNOS. Gene expression and correlation analysis in patients with cardiovascular diseases identified insulin receptor substrate 2 (IRS2) as the most correlated eNOS-ceRNA. The expression levels of eNOS and IRS2 were coincidentally increased by application of laminar shear but reduced with eNOS or IRS2 siRNA transfection in human ECs, which was impeded by Dicer siRNA treatment. Moreover, luciferase reporter assay showed that these three miRNAs directly target the 3′UTR of eNOS and IRS2. Overexpression of these three miRNAs decreased, whereas inhibition of them increased, both mRNA and protein levels of eNOS and IRS2. Functionally, silencing eNOS suppressed the Akt signal pathway, while IRS2 knockdown reduced NO production in ECs. Thus, we identified eNOS and IRS2 as ceRNAs and revealed a novel mechanism explaining the coincidence of metabolic and cardiovascular diseases.

关 键 词：ENOS ceRNA MIRNAS IRS2 ENDOTHELIAL DYSFUNCTION 

分 类 号：Q[生物学]