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(Circulation. 2009;120:1524-1532.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1

Rossella Menghini, PhD; Viviana Casagrande, BS; Marina Cardellini, MD; Eugenio Martelli, MD; Alessandro Terrinoni, PhD; Francesca Amati, PhD; Mariuca Vasa-Nicotera, MD; Arnaldo Ippoliti, MD; Giuseppe Novelli, PhD; Gerry Melino, MD; Renato Lauro, MD; Massimo Federici, MD

From the Department of Internal Medicine (R.M., V.C., M.C., R.L., M.F.), Department of Surgery (E.M., A.I.), IDI-IRCCS Biochemistry Laboratory, c/o Department of Experimental Medicine (A.T., G.M.), and Department of Biopathology and Imaging (F.A., G.N.), University of Rome Tor Vergata, Rome, Italy; and Medical Research Council (M.V.-N., G.M.), Toxicology Unit, University of Leicester, Leicester, United Kingdom.

Correspondence to Massimo Federici, MD, Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail federicm{at}uniroma2.it

Received March 13, 2009; accepted August 7, 2009.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1457-1458. [Extract] [Full Text]