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

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. Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.V.G. de Yébenes was supported by Ramón y Cajal grant RYC-2009-04503 and AECC foundation grant INVES18013GARC and by the Universidad Complutense de Madrid. S.M. Mur and A.R. Ramiro are supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC) funding. A.R. Ramiro was supported by the Spanish Ministerio de Ciencia e Innovación (PID2019-107551RB-I00), the Spanish Ministerio de Economía, Industria y Competitividad (SAF2013-42767-R and SAF2016-75511-R), and the European Research Council StG BCLYM. M. Salaices was supported by the Ministerio de Ciencia e Innovación (SAF2016-80305P) and with J. Miguel Redondo by Instituto de Salud Carlos III (CIBER de Enfermedades Cardiovasculares, CB16/11/00286 and CB16/11/00264) and Comunidad de Madrid (B2017/BMD-3676). V.G. de Yébenes was supported by Ministerio de Ciencia e Innovación (PID2019-107551RB-I00). Further support was provided by the European Social Fund and the European Regional Development Fund “A Way to Build Europe.” The CNIC is supported by Ministerio de Ciencia, Innovacion y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S