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The Role of Histone Deacetylase 9 in Vascular Calcification

组蛋白脱乙酰酶 9 在血管钙化中的作用

基本信息

批准号：
10183302
负责人：
Rajeev Malhotra
金额：
$ 63.75万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183302
关键词：
Abdomen Affect Age Arteries Atherosclerosis Attenuated Binding Binding Sites Biological Biological Assay Blood Vessels Bone Morphogenetic Proteins Cardiovascular Diseases Catalytic Domain Cells Characteristics Cohort Studies Deacetylase Deposition Development Disease Event Extracellular Matrix Family Genetic Genetic Determinism Genetic Polymorphism HDAC9 gene High Fat Diet Histone Deacetylase Human Human Genome In Vitro Knock-out Link Low Density Lipoprotein Receptor MALAT1 gene Medial Mediating Messenger RNA Modeling Molecular Morbidity - disease rate Mus Myocardial Infarction Participant Pathway interactions Peripheral arterial disease Phenotype Play Prevention Protein Deficiency Proteins Risk Role Series Signal Pathway Signaling Protein Single Nucleotide Polymorphism Smooth Muscle Myocytes Stroke Testing Untranslated RNA Vascular Diseases Vascular Smooth Muscle Vascular calcification Vesicle Whole Blood abdominal aorta base calcification calcium phosphate cardiovascular risk factor effective therapy experimental study extracellular vesicles genome wide association study in vitro Model in vivo insight matrix Gla protein member mortality mouse model myocyte-specific enhancer-binding factor 2 novel osteogenic overexpression prevent success

项目摘要

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.

项目总结