MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1

Circulation. 2009 Oct 13;120(15):1524-32. doi: 10.1161/CIRCULATIONAHA.109.864629. Epub 2009 Sep 28.

Abstract

Background: Aging is a major risk factor for the development of atherosclerosis and coronary artery disease. Through a microarray approach, we have identified a microRNA (miR-217) that is progressively expressed in endothelial cells with aging. miR-217 regulates the expression of silent information regulator 1 (SirT1), a major regulator of longevity and metabolic disorders that is progressively reduced in multiple tissues during aging.

Methods and results: miR-217 inhibits SirT1 expression through a miR-217-binding site within the 3'-UTR of SirT1. In young human umbilical vein endothelial cells, human aortic endothelial cells, and human coronary artery endothelial cells, miR-217 induces a premature senescence-like phenotype and leads to an impairment in angiogenesis via inhibition of SirT1 and modulation of FoxO1 (forkhead box O1) and endothelial nitric oxide synthase acetylation. Conversely, inhibition of miR-217 in old endothelial cells ultimately reduces senescence and increases angiogenic activity via an increase in SirT1. miR-217 is expressed in human atherosclerotic lesions and is negatively correlated with SirT1 expression and with FoxO1 acetylation status.

Conclusions: Our data pinpoint miR-217 as an endogenous inhibitor of SirT1, which promotes endothelial senescence and is potentially amenable to therapeutic manipulation for prevention of endothelial dysfunction in metabolic disorders.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Cell Line
  • Cellular Senescence / physiology*
  • Endothelial Cells / physiology*
  • Humans
  • MicroRNAs / physiology*
  • Sirtuin 1
  • Sirtuins / antagonists & inhibitors
  • Sirtuins / physiology*

Substances

  • MicroRNAs
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins