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Open Access Publications from the University of California

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

  • Author(s): Chen, Z
  • Wen, L
  • Martin, M
  • Hsu, C
  • Fang, L
  • Lin, F
  • Lin, T
  • Geary, MJ
  • Geary, GG
  • Zhao, Y
  • Johnson, DA
  • Chen, J
  • Lin, S
  • Chien, S
  • Huang, H
  • Miller, YI
  • Huang, P
  • Shyy, JYJ
  • et al.

© 2015 by the American College of Cardiology Foundation and the American Heart Association, Inc. BACKGROUND—: Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including eNOS-derived NO 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 (ECs) challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and Ang 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, Krüppel-like factor 2 (KLF2), and KLF4, leading to NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation and eNOS inhibition. In EC-specific SREBP2 transgenic mice, locked nucleic acid (LNA)-modified antisense miR-92a (LNA-92a) attenuates inflammasome, improves vasodilation, and ameliorates Ang II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with EC-dependent, flow-mediated vasodilation and is positively correlated with serum level of IL-1β. CONCLUSIONS—: Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in diagnosis and/or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

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