Menghini Rossella, Casagrande Viviana, Cardellini Marina, Martelli Eugenio, Terrinoni Alessandro, Amati Francesca, Vasa-Nicotera Mariuca, Ippoliti Arnaldo, Novelli Giuseppe, Melino Gerry, Lauro Renato, Federici Massimo
Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Circulation. 2009 Oct 13;120(15):1524-32. doi: 10.1161/CIRCULATIONAHA.109.864629. Epub 2009 Sep 28.
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.
衰老为动脉粥样硬化和冠状动脉疾病发生的主要风险因素。通过微阵列方法，我们鉴定出一种微小RNA（miR-217），其在内皮细胞中随衰老而逐渐表达。miR-217调节沉默信息调节因子1（SirT1）的表达，SirT1是长寿和代谢紊乱的主要调节因子，在衰老过程中其在多个组织中逐渐减少。
miR-217通过SirT1 3'-非翻译区内的miR-217结合位点抑制SirT1表达。在年轻的人脐静脉内皮细胞、人主动脉内皮细胞和人冠状动脉内皮细胞中，miR-217诱导过早衰老样表型，并通过抑制SirT1以及调节叉头框O1（FoxO1）和内皮型一氧化氮合酶的乙酰化作用导致血管生成受损。相反，在衰老的内皮细胞中抑制miR-217最终可通过增加SirT1来减少衰老并增加血管生成活性。miR-217在人类动脉粥样硬化病变中表达，且与SirT1表达以及FoxO1乙酰化状态呈负相关。
我们的数据明确miR-217是SirT1的内源性抑制剂，其促进内皮衰老，并且在代谢紊乱中预防内皮功能障碍方面可能适合进行治疗性干预。
