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MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1

Originally published28 Sep 2009Circulation. 2009;120:1524–1532

    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.

    Footnotes

    Correspondence to Massimo Federici, MD, Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail

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    circulationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & Wilkins
    CLINICAL PERSPECTIVE13102009

    Cellular senescence of endothelial cells has been involved in causes of atherosclerosis, although the mechanisms underlying the aging-induced attenuation of endothelial functions are unknown. On the basis of recent evidence, we hypothesized that microRNAs, a class of endogenous, small, noncoding, single-stranded RNAs of approximately 22 nucleotides that are known to negatively regulate gene expression, may be a cause of endothelial dysfunction. In the present study, we used a model of endothelial senescence to identify microRNAs associated with the aging process and to recognize their potential targets. We found that a particular microRNA, miR-217, is progressively expressed in endothelial cells during senescence. In silico analysis indicated that silent information regulator 1 (SirT1) is a potential target of miR-217. SirT1 is an NAD+-dependent deacetylase that regulates gene expression and exerts protective effects against endothelial dysfunction and metabolic syndrome. SirT1 action is lost during aging, but the cause of the age-related decline of SirT1 is unknown. Thus, in the present studies, we sought to address whether endothelial senescence is determined by a miR-217–dependent SirT1 loss of function. We observed that miR-217 inhibits SirT1 function in endothelial cells, specifically by reducing its ability to modulate the function of a transcription factor called FoxO1 that is involved in angiogenesis, apoptosis, and stress resistance. The inhibition of miR-217 rescues the phenotype of senescent endothelial cells. The evidence for such a miR-217–SirT1-FoxO1 pathway in atherosclerotic plaque from human donors has clear clinical implications for the possibility of interfering with miR-217 by use of treatments to antagonize its function in the endothelium of patients.

    The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.864629/DC1.

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