MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1

• Published in: Circulation (New York, N.Y.) N.Y.), 2009-10, Vol.120 (15), p.1524-1532
• Main Authors: MENGHINI, Rossella, CASAGRANDE, Viviana, LAURO, Renato, FEDERICI, Massimo, CARDELLINI, Marina, MARTELLI, Eugenio, TERRINONI, Alessandro, AMATI, Francesca, VASA-NICOTERA, Mariuca, IPPOLITI, Arnaldo, NOVELLI, Giuseppe, MELINO, Gerry
• Format: Article
• Language: English
• Subjects: Aging - physiology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Line; Cellular Senescence - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - physiology; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; MicroRNAs - physiology; Sirtuin 1; Sirtuins - antagonists & inhibitors; Sirtuins - physiology; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.864629

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. 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. 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.