Regulatory Role of HDAC in Post-MI Ventricular Remodeling

HDAC 在 MI 后心室重构中的调节作用

基本信息

批准号：
10830235
负责人：
Donald R. Menick
金额：
--
依托单位：
RALPH H JOHNSON VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-10-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10830235
关键词：
Acetylation Affect African American population Alcohol consumption Anti-Inflammatory Agents Appearance Area Back CD86 gene Cardiac Cause of Death Cells Cessation of life Chromatin Structure Cicatrix Clinical Treatment Communication Complex Congestive Heart Failure Coronary heart disease Data Death Rate Diabetes Mellitus EFRAC Endothelial Cells Environment Enzyme Inhibition Enzymes Equilibrium Excision Extracellular Matrix Fibroblasts Fibrosis Fostering Gene Expression Gene Expression Profiling Genetic Transcription Glycopeptides Heart Heart Diseases Heart failure Heterogeneity Histone Deacetylase Histone Deacetylase Inhibitor Hour Hypertension Infarction Inflammation Inflammation Mediators Inflammatory Injury Interleukin-10 Interleukin-4 Kinetics Lipids Macrophage Maps Matrix Metalloproteinases Mediating Modeling Molecular Myocardial Infarction Myocardial Ischemia Myocardium Myofibroblast Obesity Overweight Patients Peptide Hydrolases Peptides Phagocytes Phagocytosis Phase Phenotype Play Polysaccharides Population Population Heterogeneity Pre-Clinical Model Process Proliferating Proteolysis Regulation Repression Resolution Reverse Transcriptase Polymerase Chain Reaction Role Smoking Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Testing Therapeutic Tissues Translating United States Ventricular Function Ventricular Remodeling Veterans Woman Work cytokine epigenetic regulation healing heart damage heart disease risk histone acetyltransferase improved injured insight ischemic injury mass spectrometric imaging men monocyte mortality nanoparticle necrotic tissue neovascularization neutrophil patient population preservation programs recruit repaired response stem cells targeted delivery tissue regeneration transcription factor transcriptome translational approach treatment strategy

项目摘要

Heart disease is the leading cause of death for both men and women with over 600,000 deaths/year (25% of mortality). Coronary heart disease is the most common type of heart disease with about 715,000 patients suffering a heart attack each year. Death rates in our patient population in the southeast are even higher with African Americans having higher rates yet. Our VA patients reflect our local population with elevated risk of heart disease often presenting with hypertension, diabetes, obesity or overweight, smoking and excessive alcohol use. VA patients who have incurred LV injury due to myocardial infarction (MI) undergo ventricular remodeling, which can lead to chamber dilation and progression to congestive heart failure. Monocyte-derived macrophages are believed to play a major role in the regulation of infarct healing. Post-MI repair is made up of a biphasic process with phase I mediated by inflammatory M1 macrophages that are phagocytic, and secrete high levels of MMPs and proinflammatory mediators. By contrast the M2 macrophages produce anti-inflammatory cytokines and communicate with myofibroblasts, endothelial cells, parenchymal and local progenitor cells to help coordinate remodeling and repair of the damaged tissue. The controlled recruitment of the inflammatory monocytes and resulting macrophages is essential for proper healing, but excessive or prolonged recruitment of these inflammatory monocytes and M1 macrophage results in deleterious remodeling and heart failure. Histone deacetylases (HDACs) and histone acetyl-transferases (HATs) are critical players in regulating gene expression via modulation of chromatin structure and the acetylation of transcription factors. We and others have demonstrated that HDAC inhibition is efficacious in pre-clinical models of ischemic heart disease. Our data show HDAC inhibition in a model of MI results in the dramatic increase in the recruitment of reparative macrophages by 1 d post-MI which correlates with significantly lower LV dilation and preserves LV ejection fraction. Therefore, we hypothesize that HDACs serve as a master regulator of macrophage polarization, promoting resolution of inflammation and protection of adverse remodeling through secretion of pro- reparative factors. By bringing the HDAC activity in the injured myocardium back into balance, we change the kinetics of appearance of reparative macrophages via epigenetic regulation of macrophages and favorably influence the complex cross-talk between macrophages and neutrophils and macrophages and fibroblasts. We have 3 Aims to test our hypothesis. Aim 1 Determine how HDAC inhibition in the post MI ventricle affects macrophage phenotype, function and resulting tissue microenvironment in order to foster infarct healing. Aim 2 Determine how nanoparticle targeted delivery of HDAC inhibition to monocytes and macrophages affects the post-MI macrophage transcriptome, function and resulting tissue microenvironment. Aim 3 Determine how nanoparticle targeted delivery of HDAC inhibition to monocytes and macrophages affects the post-MI macrophage-cross talk with neutrophils and fibroblasts. Importantly, our study will give us important new molecular insights into the role of class I HDACs in regulating macrophage polarization and possibly open a new translational approach for treatment of post-MI VA patients. It is hoped that the findings of this application will be translated into new and successful clinical treatment strategies to ameliorate post-MI injury for our Veterans.

心脏病是男性和女性死亡的主要原因，每年有超过 60 万人死亡（死亡率的 25%）。冠心病是最常见的心脏病类型，约有每年有 715,000 名患者心脏病发作。我们的患者群体的死亡率东南部的比例甚至更高，其中非裔美国人的比例更高。我们的 VA 患者反映了我们的心脏病风险较高的当地人群经常出现高血压、糖尿病、肥胖或超重、吸烟和过量饮酒。发生左心室损伤的 VA 患者由于心肌梗塞 (MI) 发生心室重塑，从而导致心室扩张并进展为充血性心力衰竭。单核细胞衍生的巨噬细胞被认为发挥着在梗塞愈合的调节中起主要作用。 MI 后修复由双相过程组成 I 期由炎症性 M1 巨噬细胞介导，这些巨噬细胞具有吞噬能力，并分泌高水平的 MMP 和促炎介质。相比之下，M2 巨噬细胞产生抗炎作用细胞因子并与肌成纤维细胞、内皮细胞、实质细胞和局部祖细胞通讯细胞帮助协调受损组织的重塑和修复。控制招募炎性单核细胞和由此产生的巨噬细胞对于正常愈合至关重要，但过多或过多这些炎症单核细胞和 M1 巨噬细胞的长期募集会导致有害的结果重塑和心力衰竭。组蛋白脱乙酰酶 (HDAC) 和组蛋白乙酰转移酶 (HAT) 是通过调节染色质结构来调节基因表达的关键参与者转录因子的乙酰化。我们和其他人已经证明 HDAC 抑制是在缺血性心脏病的临床前模型中有效。我们的数据显示模型中的 HDAC 抑制 MI 导致 MI 后 1 d 修复性巨噬细胞的募集急剧增加这与显着降低的 LV 扩张相关并保留 LV 射血分数。因此，我们假设 HDAC 作为巨噬细胞极化的主要调节器，促进通过分泌促炎症因子来解决炎症并保护不良重塑修复因素。通过使受损心肌中的 HDAC 活性恢复平衡，我们通过表观遗传调节改变修复性巨噬细胞的出现动力学巨噬细胞并有利地影响巨噬细胞和中性粒细胞之间的复杂串扰以及巨噬细胞和成纤维细胞。我们有 3 个目标来检验我们的假设。目标 1 确定 HDAC 如何 MI 后心室的抑制影响巨噬细胞表型、功能和所得组织微环境以促进梗塞愈合。目标 2 确定纳米颗粒如何靶向递送 HDAC 对单核细胞和巨噬细胞的抑制影响 MI 后巨噬细胞转录组，功能和由此产生的组织微环境。目标 3 确定纳米颗粒如何靶向递送 HDAC 对单核细胞和巨噬细胞的抑制影响 MI 后巨噬细胞与中性粒细胞和成纤维细胞。重要的是，我们的研究将为我们提供重要的新分子见解 I 类 HDAC 在调节巨噬细胞极化中的作用并可能开辟新的转化途径 MI VA 后患者的治疗方法。希望本申请的结果能够转化为新的、成功的临床治疗策略，以改善我们的心肌梗死后损伤退伍军人。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

1-[(3-Methyl-piperidin-1-yl)(3-nitro-phen-yl)meth-yl]naphthalen-2-ol.

1-[(3-甲基-哌啶-1-基)(3-硝基-苯-基)甲基]萘-2-醇。

DOI：
10.1107/s1600536810045149
发表时间：
2010
期刊：
Acta crystallographica. Section E, Structure reports online
影响因子：
0
作者：
Chen,JinMei;Zhao,Hong
通讯作者：
Zhao,Hong

Nanowires and Electrical Stimulation Synergistically Improve Functions of hiPSC Cardiac Spheroids.

DOI：
10.1021/acs.nanolett.6b02093
发表时间：
2016-07-13
期刊：
Nano letters
影响因子：
10.8
作者：
Richards DJ;Tan Y;Coyle R;Li Y;Xu R;Yeung N;Parker A;Menick DR;Tian B;Mei Y
通讯作者：
Mei Y

Silicon nanowire-induced maturation of cardiomyocytes derived from human induced pluripotent stem cells.

DOI：
10.1021/nl502227a
发表时间：
2015-05-13
期刊：
Nano letters
影响因子：
10.8
作者：
Tan Y;Richards D;Xu R;Stewart-Clark S;Mani SK;Borg TK;Menick DR;Tian B;Mei Y
通讯作者：
Mei Y

Cell number per spheroid and electrical conductivity of nanowires influence the function of silicon nanowired human cardiac spheroids.