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 knoc...

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Published in:Arteriosclerosis, thrombosis, and vascular biology Vol. 40; no. 10; p. 2408
Main Authors: de Yébenes, Virginia G, Briones, Ana M, Martos-Folgado, Inmaculada, Mur, Sonia M, Oller, Jorge, Bilal, Faiz, González-Amor, María, Méndez-Barbero, Nerea, Silla-Castro, Juan Carlos, Were, Felipe, Jiménez-Borreguero, Luis J, Sánchez-Cabo, Fátima, Bueno, Héctor, Salaices, Mercedes, Redondo, Juan Miguel, Ramiro, Almudena R
Format: Journal Article
Language:English
Published: 01.10.2020
ISSN:1524-4636, 1524-4636
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Summary: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.OBJECTIVEmicroRNAs 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.CONCLUSIONSOur results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.
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ISSN:1524-4636
1524-4636
DOI:10.1161/ATVBAHA.120.314333