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

Arterioscler Thromb Vasc Biol. 2020 Oct;40(10):2408-2424. doi: 10.1161/ATVBAHA.120.314333. Epub 2020 Aug 27.


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.

Keywords: RNA, untranslated; apolipoproteins E; atherosclerosis; cardiovascular diseases; coronary artery disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged, 80 and over
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Case-Control Studies
  • Cells, Cultured
  • Coronary Artery Disease / genetics
  • Coronary Artery Disease / metabolism
  • Disease Models, Animal
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Female
  • Hemodynamics
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • MicroRNAs / blood
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Plaque, Atherosclerotic*
  • Signal Transduction
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left


  • MIRN-217 microRNA, mouse
  • MIRN217 microRNA, human
  • MicroRNAs
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse