The Role of Histone Deacetylase 9 in Vascular Calcification

项目摘要 血管钙化是心肌梗死等动脉粥样硬化性心血管疾病的标志 和中风，它们是世界上发病率和死亡率的主要原因。虽然主动脉钙化是 心血管疾病的一个强有力的独立危险因素，主动脉钙化的遗传决定因素 血管钙化的分子机制尚未完全阐明。中 在一项超过9400名参与者的多队列研究中，我们发现了单核苷酸多态性， 组蛋白脱乙酰酶9（HDAC 9）基因座与腹主动脉钙化相关。在体外 在钙化模型中，我们的初步实验表明，HDAC 9的抑制可以防止钙化。 主动脉血管平滑肌细胞（VSMC）钙化。在两种不同的小鼠模型中，我们发现， HDAC 9缺乏可防止血管钙化和动脉粥样硬化的发展。 基于我们的初步证据，结合人类全基因组关联研究，体外VSMC 实验，和血管钙化的小鼠模型，我们已经确定HDAC 9作为一种新的激活剂， 血管钙化本提案的总体目标是通过以下方式了解分子机制： 其中HDAC 9促进血管钙化和动脉粥样硬化。HDAC 9是IIa类的成员 HDAC家族，所有这些都具有脱乙酰酶催化结构域和肌细胞增强因子2 （MEF 2）结合位点。首先，使用一系列VSMC功能测定，我们建议确定 HDAC 9及其下游靶点MEF 2促进VSMC成骨表型转换和钙化。 第二，为了检验HDAC 9对血管疾病的影响是通过其特异性表达来发挥的这一假设， 我们将确定在鼠模型中VSMC特异性HDAC 9缺失是否足以 减轻血管钙化和动脉粥样硬化。最后，我们发现了一种新的相互作用， HDAC 9和长非编码RNA MALAT 1。我们将确定HDAC 9是否需要MALAT 1- 使用MALAT 1对VSMC表型和血管钙化及动脉粥样硬化的依赖性影响 小鼠敲除模型。提出的实验将提供重要的机制见解的功能 HDAC 9在血管系统中的表达以及血管生成的潜在分子和细胞机制 钙化和动脉粥样硬化。

Project Summary Vascular calcification is a hallmark of atherosclerotic cardiovascular diseases such as myocardial infarction and stroke, which are the leading causes of morbidity and mortality in the world. Although aortic calcification is a strong independent risk factor for cardiovascular disease, the genetic determinants of aortic calcification remain unknown and the molecular mechanisms of vascular calcification are incompletely elucidated. In a multi-cohort study with more than 9400 participants, we identified single nucleotide polymorphisms in the histone deacetylase 9 (HDAC9) locus that are associated with abdominal aortic calcification. In an in vitro model of calcification, our preliminary experiments demonstrated that inhibition of HDAC9 prevented the calcification of aortic vascular smooth muscle cells (VSMCs). In two different mouse models, we found that global HDAC9 deficiency protected against the development of vascular calcification and atherosclerosis. Based on our preliminary evidence, combining a human genome-wide association study, in vitro VSMC experiments, and a murine model of vascular calcification, we have identified HDAC9 as a novel activator of vascular calcification. The overall objective of this proposal is to understand the molecular mechanisms by which HDAC9 promotes vascular calcification and atherosclerosis. HDAC9 is a member of the Class IIa HDAC family, all of which possess both a deacetylase catalytic domain and a myocyte enhancer factor 2 (MEF2) binding site. First, using a series of VSMC functional assays, we propose to determine the role of HDAC9, and its downstream target MEF2, in promoting VSMC osteogenic phenotype switch and calcification. Second, to test the hypothesis that the influence of HDAC9 on vascular disease is exerted through its specific effects on VSMCs, we will determine if VSMC-specific deletion of HDAC9 in a murine model is sufficient to attenuate vascular calcification and atherosclerosis. Lastly, we have uncovered a novel interaction between HDAC9 and the long non-coding RNA MALAT1. We will determine if MALAT1 is required for the HDAC9- dependent effects on VSMC phenotype and on vascular calcification and atherosclerosis using a MALAT1 murine knockout model. The experiments proposed will provide important mechanistic insights into the function of HDAC9 in the vasculature and into the underlying molecular and cellular mechanisms of vascular calcification and atherosclerosis.