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.
Menghini
Rossella
R
Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Casagrande
Viviana
V
Cardellini
Marina
M
Martelli
Eugenio
E
Terrinoni
Alessandro
A
Amati
Francesca
F
Vasa-Nicotera
Mariuca
M
Ippoliti
Arnaldo
A
Novelli
Giuseppe
G
Melino
Gerry
G
Lauro
Renato
R
Federici
Massimo
M
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