Role of SIRT6 in calcific aortic valve disease

描述（由申请人提供）：衰老与心血管钙化的进行性增加相关1。血流动力学显著的主动脉瓣狭窄影响3%的65岁以上人群。即使是中度主动脉瓣狭窄（峰值速度为3-4 m/sec）的患者，5年无事件生存率也低于40%，唯一批准的治疗方法是瓣膜置换术。然而，最近的工作描述了成骨细胞样细胞，破骨细胞样细胞和骨基质在钙化的主动脉瓣中的存在，这表明瓣膜钙化是一个活跃的，潜在的可改变的过程。我们小组的初步数据表明，钙化的主动脉瓣细胞中存在大量的表观遗传修饰。具体地说，沉默调节蛋白6的表达在狭窄瓣膜中显著降低，并且与蛋白质和组蛋白乙酰化的增加强烈相关。在实验中，小鼠中SIRT 6的整体缺失导致显著的早衰症表型，并且患有早衰症综合征的患者具有更大的心血管钙化发展倾向。由于许多瓣膜钙化的危险因素与氧化应激增加有关，我们还试图确定氧化应激增加与组蛋白乙酰化/去乙酰化酶活性之间是否存在联系。因此，本申请的目的是通过实验确定：1）氧化应激的增加是否增加组蛋白乙酰化并加速主动脉瓣钙化和狭窄的进展，2）改变SIRT 6水平是否加速或减缓高胆固醇血症小鼠中主动脉瓣狭窄的进展，和3）血管内皮或神经嵴衍生细胞中SIRT 6的缺失（即，形成主动脉瓣的细胞 和流出道）加速CAVS的进展。我们将使用新的体内动物模型和体外方法相结合，以确定氧化应激和SIRT 6影响主动脉瓣成骨细胞/成骨样细胞分化和活性的机制。通过使用这些方法来确定减缓钙化性主动脉瓣疾病进展的机制，我们希望确定将改善人类寿命和健康范围的疗法。

DESCRIPTION (provided by applicant): Aging is associated with progressive increases in cardiovascular calcification1. Hemodynamically significant aortic valve stenosis affects 3% of the population over age 65. Patients with even moderate aortic valve stenosis (peak velocity of 3-4 m/sec) have a 5 year event-free survival of less than 40%, with the only approved treatment being valve replacement surgery. Recent work, however, described the presence of osteoblast-like cells, osteoclast-like cells, and bone matrix in calcified aortic valves, which suggests that valve calcification is an active, potentially modifiable process. Preliminary data from our group suggest that there are substantial epigenetic modifications present in cells from calcified aortic valves. Specifically, expression of sirtuin 6 is markedly reduced in stenotic valves and strongly associated with increases in protein and histone acetylation. Experimentally, global deletion of SIRT6 in mice results in a dramatic progeroid phenotype, and patients with progeroid syndromes have a much greater propensity for development of cardiovascular calcification. As many risk factors for valve calcification are associated with increases in oxidative stress, we also sought to determine whether there is a link between increases in oxidative stress and histone acetylation/sirtuin activity. Thus, the aims of the current application is to experimentall determine whether: 1) increases in oxidative stress increase histone acetylation and accelerate progression of aortic valve calcification and stenosis, 2) altering SIRT6 levels accelerates or slows progression of aortic valve stenosis in hypercholesterolemic mice, and 3) deletion of SIRT6 in vascular endothelium or neural crest-derived cells (i.e., cells that form the aortic valve and outflow tract) accelerate progression of CAVS. We will use a combination of novel in vivo animal models and in vitro methods to identify mechanisms whereby oxidative stress and SIRT6 impact osteoblast/osteoblast-like cell differentiation and activity in aortic valves. By using thes approaches to identify mechanisms that slow the progression of calcific aortic valve disease, we hope to identify therapies that will improve both the lifespan and health span of humans.