MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1

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.