Regulatory Role of HDAC in Post-MI Ventricular Remodeling

HDAC 在 MI 后心室重构中的调节作用

• 批准号: 10265359
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265359
• 关键词: Acetylation; Affect; African American; Alcohol consumption; Anti-Inflammatory Agents; Appearance; Area; Back; CD86 gene; Cardiac; Cause of Death; Cells; Cessation of life; Chromatin Structure; Cicatrix; Clinical Treatment; 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; Histones; Hour; Hypertension; Image; Infarction; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-4; Kinetics; Lead; Lipids; Maps; Mass Spectrum Analysis; Matrix Metalloproteinases; Mediating; Mediator of activation protein; 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; Proteolysis; Regulation; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Smoking; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Testing; Therapeutic; Tissues; Transferase; Translating; United States; Ventricular Function; Ventricular Remodeling; Veterans; Woman; Work; cytokine; epigenetic regulation; healing; heart damage; heart disease risk; improved; injured; insight; ischemic injury; macrophage; men; monocyte; mortality; nanoparticle; necrotic tissue; neovascularization; neutrophil; patient population; preservation; recruit; repaired; response; stem cells; targeted delivery; tissue regeneration; transcription factor; transcriptome; translational approach; treatment strategy

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的主要死因，每年有60多万人死亡。 (25死亡率）。冠心病是最常见的心脏病类型， 每年有715，000名患者患有心脏病。我们的患者人群中的死亡率 东南部甚至更高，非洲裔美国人的比率更高。我们的VA患者反映了我们的 心脏病风险增加的本地人口，通常表现为高血压，糖尿病， 肥胖或超重，吸烟和过度饮酒。发生LV损伤的VA患者 由于心肌梗死（MI）发生心室重构，这可能导致腔室扩张 并发展为充血性心力衰竭单核细胞衍生的巨噬细胞被认为是一种 在调节梗死愈合中的主要作用。MI后修复由双相过程组成， I期由炎性M1巨噬细胞介导，所述巨噬细胞是吞噬细胞，并分泌高水平的 MMPs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沟通 细胞来帮助协调重建和修复受损组织。有控制地招募 炎性单核细胞和产生的巨噬细胞对于适当的愈合是必不可少的，但过度或 这些炎性单核细胞和M1巨噬细胞的长期募集导致有害的 重塑和心力衰竭组蛋白去乙酰化酶（HDAC）和组蛋白乙酰转移酶（HAT） 是通过调节染色质结构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HDAC抑制模型 心肌梗死后1天， 这与显著较低的LV扩张相关并保持LV射血分数。所以我们 假设HDAC作为巨噬细胞极化主要调节剂，促进 通过分泌促炎症因子来缓解炎症和保护不良重塑， 修复因素。通过使受损心肌中的HDAC活性恢复平衡， 通过表观遗传调节改变修复性巨噬细胞的出现动力学 并有利地影响巨噬细胞和中性粒细胞之间的复杂的串扰 以及巨噬细胞和成纤维细胞。我们有三个目标来验证我们的假设。目标1确定HDAC如何 MI后心室中的抑制作用影响巨噬细胞表型、功能和产生的组织 微环境，以促进梗死愈合。目的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作用影响MI后巨噬细胞转录组， 功能和产生的组织微环境。目的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作用影响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HDACs在调节巨噬细胞极化中的作用，并可能打开一个新的翻译途径， MI后VA患者的治疗方法。希望这项申请的结果将 转化为新的和成功的临床治疗策略，以改善心肌梗死后损伤， 老兵