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：
10418758
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418758
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.

项目概要血管钙化是心肌梗塞等动脉粥样硬化性心血管疾病的标志和中风，这是世界上发病和死亡的主要原因。虽然主动脉钙化心血管疾病的一个强大的独立危险因素，主动脉钙化的遗传决定因素仍然未知，血管钙化的分子机制尚未完全阐明。在一个通过超过 9400 名参与者的多队列研究，我们发现了单核苷酸多态性与腹主动脉钙化相关的组蛋白脱乙酰酶 9 (HDAC9) 位点。在体外钙化模型中，我们的初步实验表明，抑制 HDAC9 可以阻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，我们发现整体 HDAC9 缺乏可以防止血管钙化和动脉粥样硬化的发展。根据我们的初步证据，结合人类全基因组关联研究，体外 VSMC 通过实验和小鼠血管钙化模型，我们发现 HDAC9 是一种新型的血管钙化激活剂。血管钙化。该提案的总体目标是通过以下方式了解分子机制：其中HDAC9促进血管钙化和动脉粥样硬化。 HDAC9 是 IIa 类成员 HDAC 家族，均具有脱乙酰酶催化结构域和肌细胞增强因子 2 (MEF2) 结合位点。首先，使用一系列 VSMC 功能测定，我们建议确定 HDAC9 及其下游靶点 MEF2，促进 VSMC 成骨表型转换和钙化。其次，检验 HDAC9 对血管疾病的影响是通过其特定的机制发挥作用的假设。对 VSMC 的影响，我们将确定在小鼠模型中 VSMC 特异性删除 HDAC9 是否足以减轻血管钙化和动脉粥样硬化。最后，我们发现了一种新颖的相互作用 HDAC9 和长非编码 RNA MALAT1。我们将确定 HDAC9 是否需要 MALAT1- 使用 MALAT1 对 VSMC 表型以及血管钙化和动脉粥样硬化的依赖性影响小鼠敲除模型。所提出的实验将为该功能提供重要的机制见解 HDAC9 在血管系统中的表达以及血管的潜在分子和细胞机制钙化和动脉粥样硬化。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estimating Risk of Mechanical Ventilation and Mortality Among Adult COVID-19 patients Admitted to Mass General Brigham: The VICE and DICE Scores.

估计麻省总医院布里格姆总医院成人 COVID-19 患者机械通气和死亡的风险：VICE 和 DICE 评分。

DOI：
发表时间：
2020-09-16
期刊：
影响因子：
0
作者：
Nicholson, Christopher J;Wooster, Luke;Sigurslid, Haakon H;Li, Rebecca F;Jiang, Wanlin;Tian, Wenjie;Cardenas, Christian L Lino;Malhotra, Rajeev
通讯作者：
Malhotra, Rajeev

Predictors for Rapid Progression of Coronary Calcification: An Optical Coherence Tomography Study.

冠状动脉钙化快速进展的预测因素：光学相干断层扫描研究。

DOI：
发表时间：
2021
期刊：
影响因子：
5.4
作者：
Nakajima, Akihiro;Araki, Makoto;Kurihara, Osamu;Minami, Yoshiyasu;Soeda, Tsunenari;Yonetsu, Taishi;Higuma, Takumi;Kakuta, Tsunekazu;McNulty, Iris;Lee, Hang;Malhotra, Rajeev;Nakamura, Sunao;Jang, Ik
通讯作者：
Jang, Ik

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

使用 GSK343 通过增强自噬治疗钙化动脉疾病。

DOI：
发表时间：
2023-11-17
期刊：
影响因子：
5.8
作者：
Lino Cardenas, Christian L;Jiang, Wanlin;Kajuluri, Lova P;Singh, Kuldeep;Ostrom, Katrina;Li, Rebecca;Cherbonneau, Francois;Boerboom, Sophie;Birchenough, Claire;Roh, Kangsan;Chou, Elizabeth L;Shahrooz, Zarbafian;Nicholson, Christopher;Johnson
通讯作者：
Johnson

Structural and functional analysis of female sex hormones against SARS-Cov2 cell entry.

女性性激素对抗 SARS-Cov2 细胞进入的结构和功能分析。

DOI：
发表时间：
2020-07-29
期刊：
影响因子：
0
作者：
Aguilar;Albaghdadi, Mazen;Jiang, Wanlin;Lopez, Karin J Vera;Del;Valdez, Badhin Gómez;Lindsay, Mark E;Malhotra, Rajeev;Lino Cardenas, Christian L
通讯作者：
Lino Cardenas, Christian L