Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction
Virginia G. de Yébenes, Ana M. Briones, Inmaculada Martos-Folgado, Sonia M. Mur, Jorge Oller, Faiz Bilal, María González‐Amor, Nerea Méndez‐Barbero, Juan Carlos Silla-Castro, Felipe Were, Luis Jesús Jiménez‐Borreguero, Fátima Sánchez‐Cabo, Héctor Bueno, Mercedes Salaíces, Juan Miguel Redondo, Almudena R. Ramiro
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.