MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation

Jing Zhou, Kuei Chun Wang, Wei Wu, Shankar Subramaniam, John Y.J. Shyy, Jeng Jiann Chiu, Julie Y.S. Li, Shu Chien

研究成果: 雜誌貢獻文章

241 引文 斯高帕斯(Scopus)

摘要

Adhesion of circulating monocytes to vascular endothelial cells (ECs) is a critical event leading to vascular inflammation and, hence, development of atherosclerosis. MicroRNAs (miRs) are a class of endogenous, highly conserved, noncoding small RNAs that play important roles in regulating gene expression and cellular function, as well as pathogenesis of atherosclerosis. Here, we showed that oscillatory shear stress (OSS) induces the expression of miR-21 at the transcriptional level in cultured human umbilical vein ECs via an increased binding of c-Jun, which is a component of transcription factor activator protein-1 (AP-1), to the promoter region of miR-21. OSS induction of miR-21 inhibited the translation, but not transcription, of peroxisome proliferators-activated receptor-α (PPARα) by 3′-UTR targeting. Overexpression of miR-21 up-regulated AP-1 activation, which was attenuated by exogenous expression of PPARα. OSS and overexpression of miR-21 enhanced the expression of adhesion molecules vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and the consequential adhesion ofmonocytes to ECs. Overexpression of PPARα significantly attenuated the AP-1-mediated miR-21 expression. These results demonstrate a unique mechanism by which OSS induces AP-1 - dependent miR-21 expression, which directly targets PPARα to inhibit its expression, thereby allowing activation of AP-1 and the promotion of monocyte adhesion. Our findings suggest the presence of a positive feedback loop that enables the sustained induction of miR-21, thus contributing to the proinflammatory responses of vascular endothelium under OSS.

原文英語
頁(從 - 到)10355-10360
頁數6
期刊Proceedings of the National Academy of Sciences of the United States of America
108
發行號25
DOIs
出版狀態已發佈 - 六月 21 2011
對外發佈Yes

ASJC Scopus subject areas

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