Oxidative Stress Activates Endothelial Innate Immunity via Sterol Regulatory Element Binding Protein 2 (SREBP2) Transactivation of MicroRNA-92a

Zhen Chen, Liang Wen, Marcy Martin, Chien-Yi Hsu, Longhou Fang, Feng Mao Lin, Ting Yang Lin, McKenna J. Geary, Greg G. Geary, Yongli Zhao, David A. Johnson, Jaw-Wen Chen, Shing-Jong Lin, Shu Chien, Yury I. Miller, Hsien-Da Huang, Po-Hsun Huang, Shyy John Y. -J.

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Background-Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium.

Methods and Results-Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Kruppel-like factor 2, and Kruppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1 beta.
Original languageEnglish
Pages (from-to)805-U125
JournalCirculation
Volume131
Issue number9
DOIs
StatePublished - 3 Mar 2015

Keywords

  • endothelium; inflammasomes; microRNA-92; oxidative stress; sterol regulatory element binding protein 2

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