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: 10455524
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455524
• 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; 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; Infarction; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-4; Kinetics; Lead; Lipids; Maps; 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; mass spectrometric imaging; 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; 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; 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; Infarction; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-4; Kinetics; Lead; Lipids; Maps; 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; mass spectrometric imaging; 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死亡的主要原因，年龄超过60万人 （死亡率的25％）。冠心病是心脏病最常见的类型 每年有715,000名患者心脏病发作。我们患者人群的死亡率 由于非洲裔美国人的比率较高，东南部甚至更高。我们的VA患者反映了我们的 心脏病风险升​​高的当地人口通常出现高血压，糖尿病， 肥胖或超重，吸烟和过度使用酒精。 VA患者患有LV损伤的患者 由于心肌梗塞（MI）进行心室重塑，这可能导致腔室扩张 并发展为充血性心力衰竭。据信单核细胞衍生的巨噬细胞发挥 在梗塞愈合调节中的主要作用。 MI后维修是由双相过程组成的 I期由吞噬细胞的炎症M1巨噬细胞介导的，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 细胞因子并与肌纤维细胞，内皮细胞，实质和局部祖细胞进行通信 细胞帮助协调受损组织的重塑和修复。受控招聘 炎症性单核细胞和产生的巨噬细胞对于适当的愈合至关重要，但过度或 这些炎症单核细胞和M1巨噬细胞的长期募集导致有害 重塑和心力衰竭。组蛋白脱乙酰基酶（HDAC）和组蛋白乙酰基转移酶（HATS） 是通过调节染色质结构和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的of导致MI募集的募集急剧增加 与LV扩张显着相关并保留LV射血分数。因此，我们 假设HDAC是巨噬细胞极化的主要调节剂，促进 通过分泌炎症和保护不良重塑的保护 修复因素。通过使受伤的心肌中的HDAC活动恢复平衡，我们 通过表观遗传调节来改变修复巨噬细胞的外观动力学 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个旨在检验我们的假设的目标。 AIM 1确定HDAC如何 MI后心室的抑制作用会影响巨噬细胞表型，功能和结果组织 微环境为了促进梗塞愈合。 AIM 2确定纳米颗粒如何靶向输送 对单核细胞和巨噬细胞的HDAC抑制会影响MI后巨噬细胞转录组， 功能和产生的组织微环境。 AIM 3确定纳米颗粒如何针对输送 HDAC对单核细胞和巨噬细胞的抑制会影响MI后巨噬细胞交谈 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，并可能打开新的翻译 治疗MI后VA患者的方法。希望该应用程序的发现将是 转化为新的成功的临床治疗策略，以改善我们的MI后伤害 退伍军人。