Sciacca Sergio, Pilato Michele, Mazzoccoli Gianluigi, Pazienza Valerio, Vinciguerra Manlio
Department of Cardio-Thoracic Surgery, Mediterranean Institute for Transplantation and Advanced Therapies (ISMETT), University of Pittsburgh Medical Center (UPMC), 90127, Palermo, Italy.
Heart Vessels. 2013 Mar;28(2):268-75. doi: 10.1007/s00380-012-0238-5. Epub 2012 Feb 28.
About 1-2% of the population present with bicuspid aortic valves (BAV), a defect of the aortic valve resulting in the formation of two leaflets instead of three. This disease leads to an abnormal aorta, altered in strength and size, which in turn is a high risk factor for potentially lethal events such as aortic dissection and aneurysm formation. BAV is inheritable, with a demonstrated association with Notch1, a member of the Notch intercellular signaling pathway that is implicated in various cardiovascular disorders. Sirtuin 1 (SirT1) is a protein deacetylase of the sirtuin family, whose activation appears beneficial for cardiac diseases. A recent study has shown that SirT1 can limit Notch signaling in model systems of vascular growth. If a concomitant dysregulation in Notch and SirT1 signaling pathways can cause the phenotypic form of human BAV is unknown. To address this issue, we analyzed human ascending aorta biopsies from BAV and control patients obtained at the time of cardiac surgery. RNA and proteins were extracted from formalin-fixed and paraffin-embedded specimens, and quantitative real-time PCR and immunoblotting were used to determine the expression of sirtuins and members of the Notch family of proteins. We found a significant increase in SirT1 expression that correlates with a decreased expression of the Notch signaling effectors detected. We put forward the idea that an altered interaction between SirT1 and Notch signaling could participate in BAV pathogenesis and that these molecules could be used as potential clinical markers.
约1%-2%的人群存在二叶式主动脉瓣（BAV），这是一种主动脉瓣缺陷，导致形成两片瓣叶而非正常的三片。这种疾病会致使主动脉异常，强度和尺寸发生改变，进而成为诸如主动脉夹层和动脉瘤形成等潜在致命事件的高风险因素。BAV具有遗传性，已证实与Notch1相关，Notch1是Notch细胞间信号通路的成员，与多种心血管疾病有关。沉默调节蛋白1（SirT1）是沉默调节蛋白家族的一种蛋白质去乙酰化酶，其激活似乎对心脏疾病有益。最近一项研究表明，在血管生长模型系统中，SirT1可限制Notch信号传导。目前尚不清楚Notch和SirT1信号通路的协同失调是否会导致人类BAV的表型。为解决这一问题，我们分析了心脏手术时获取的BAV患者和对照患者的升主动脉活检样本。从福尔马林固定、石蜡包埋的标本中提取RNA和蛋白质，采用定量实时PCR和免疫印迹法测定沉默调节蛋白和Notch蛋白家族成员的表达。我们发现SirT1表达显著增加，这与检测到的Notch信号效应器表达降低相关。我们提出这样的观点，即SirT1与Notch信号之间相互作用的改变可能参与BAV的发病机制，并且这些分子可作为潜在的临床标志物。
