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.


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.
Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Rossella
R
Menghini
Viviana
V
Casagrande
Marina
M
Cardellini
Eugenio
E
Martelli
Alessandro
A
Terrinoni
Francesca
F
Amati
Mariuca
M
Vasa-Nicotera
Arnaldo
A
Ippoliti
Giuseppe
G
Novelli
Gerry
G
Melino
Renato
R
Lauro
Massimo
M
Federici
D000375:Aging / Q000502:physiology; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000502:physiology*
D035683:MicroRNAs; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins