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

Abstract

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.

Endothelial fluid shear stress sensing in vascular health and disease

“…Activation of this pathway results in IL-1β production, an important contributor to atherosclerosis that is currently targeted in clinical trials (61). Effects of SREBP2 require expression of miR-92a, which targets a number of atheroprotective mediators (62). Despite the diversity of inflammatory events triggered by disturbed flow, it should be kept in mind that the effects are not one-sided.…”

Malondialdehyde-Modified Low Density Lipoprotein as Oxidative-Stress Marker in Vasospastic Angina Patients

“…24) It is conceivable that the oxidative marker MDA-LDL may be associated with endothelial dysfunction in the mechanism of VSA because oxidative stress can generally induce endothelial dysfunction. 26) Actually, oxidized LDL is reported to be associated with endothelial dysfunction in previous myocardial infarctions. 32) In our study, the serum MDA-LDL level was high in definite VSA patients or clinical VSA, and had a positive correlation with not only T-Chol and LDL-C, but also triglycerides and fasting blood glucose.…”

“…24) Oxidative stress may induce endothelial dysfunction 25,26) and subsequent vascular spasms, and MDA-LDL might also be involved in the mechanism of VSA. However, it has not yet been determined whether MDA-LDL is associated with the clinical status of VSA.…”

Protective effect of microRNA-138 against cerebral ischemia/reperfusion injury in rats

“…It is speculated that oxidative radical-induced inflammation is crucially involved during the progression of CIR injury (17). Since miRs were identified as common regulators of DNA transcription and mRNA translation, numerous miRs have been associated with oxidative radical-mediated pathophysiological alterations (19). As a crucial protein in IR-induced injury, Lcn-2 is included in the list of miR-138 targets (20).…”