Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction

Abstract

OBJECTIVE: microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR 217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. APPROACH AND RESULTS: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR 217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE¿/¿ mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE¿/¿ mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. CONCLUSIONS: Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease. GRAPHIC ABSTRACT: A graphic abstract is available for this article. Key Words: apolipoproteins E ¿ atherosclerosis ¿ cardiovascular diseases ¿ coronary artery disease ¿ RNA, untranslated