Abstract 92: Oxidative Stress Induces Endothelial Dysfunction: Role of Sterol Regulatory Element Binding Protein 2 and MicroRNA-92a
Oxidative stress, elevated in pathophysiological conditions such as hypertension, hyperlipidemia, and aging affects endothelial homeostasis by impairing endothelial nitric oxide synthase (eNOS)-derived NO bioavailability and promoting inflammatory response. We recently demonstrated that atheroprone flow activates sterol regulatory element binding protein (SREBP) 2 and induces endothelial innate immunity, evidenced by NLRP3 inflammasome activation. Transgenic mice overexpressing endothelium-specific SREBP2 (EC-SREBP2) manifest accelerated atherosclerosis synergized by hyperlipidemia. In the current study, we investigated whether oxidative stress activates SREBP2 in endothelial cells (ECs), contributing to endothelial dysfunction. Several oxidative stress-inducing stimuli, i.e. hydrogen peroxide, Angiotensin II, and oxidized-LDL, all activates SREBP2 in ECs. Furthermore, SREBP2 transactivates microRNA-92a (miR-92a), previously shown to be dysregulated in ischemia and atherosclerosis. Chromatin immunoprecipitation, together with gain- and loss-of-function assays revealed that oxidative stress-activated SREBP2 induces miR-92a, which in turn targets several key molecules including Kruppel-like factor (KLF) 2, KLF4, and Sirtuin 1. As a result, NLRP3 inflammasome is activated and eNOS inhibited. In EC-SREBP2 mice, locked nucleic acid (LNA) inhibition of miR-92a improves vasodilatory function. In an Angiotensin II-challenged model, LNA-92a ameliorates atherogenesis in EC-SREBP2 with an ApoE-/- background. Collectively, these findings suggest a novel link between oxidative stress and the endothelial inflammation involving SREBP2-miR-92a-inflammasome. This newly defined pathway could be a therapeutic target to intervene endothelial dysfunction during the onset of atherosclerosis.
Author Disclosures: Z. Chen: None. L. Wen: None. J. Shyy: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.