Regulatory Role of HDAC in Post-MI Ventricular Remodeling

心脏病是男性和女性的主要死亡原因，每年有60多万人死亡 (死亡率的25%)。冠心病是最常见的心脏病类型，约有 每年有71.5万名心脏病患者。我们的患者群体中的死亡率 东南部的比例甚至更高，非洲裔美国人的比例更高。我们的退伍军人管理局患者反映了我们的 心脏病风险增加的当地人群通常表现为高血压、糖尿病、 肥胖或超重、吸烟和过度饮酒。曾发生左心室损伤的VA患者 由于心肌梗死(MI)经历了心室重构，这可能导致心腔扩张 并进展为充血性心力衰竭。单核细胞来源的巨噬细胞被认为扮演着 在脑梗塞愈合的调节中起主要作用。心肌梗死后修复由两个阶段的过程组成 I期由炎性M1巨噬细胞介导，这些巨噬细胞是吞噬细胞，并分泌高水平的 基质金属蛋白酶和促炎介质。相比之下，M2巨噬细胞产生抗炎作用 细胞因子与肌成纤维细胞、内皮细胞、实质细胞和局部祖细胞的通讯 帮助协调受损组织的重塑和修复的细胞。受控人员的招募 炎性单核细胞和由此产生的巨噬细胞是正常愈合所必需的，但过量或 这些炎性单核细胞和M1巨噬细胞的长期募集会导致有害的 重塑和心力衰竭。组蛋白脱乙酰酶(HDAC)和组蛋白乙酰转移酶(HATS) 是通过调节染色质结构调节基因表达的关键角色 转录因子的乙酰化。我们和其他人已经证明了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，在一个模型中，HDAC抑制 心肌梗死后1d修复性巨噬细胞募集显著增加 这与显著降低的左心室扩张和保留左心室射血分数相关。因此，我们 假设HDAC作为巨噬细胞极化的主调节器，促进 通过分泌前列环素消退炎症和保护不良重塑 补救因素。通过使受损心肌中的HDAC活性恢复平衡，我们 通过表观遗传调控改变修复性巨噬细胞的出现动力学 并有利于影响巨噬细胞和中性粒细胞之间复杂的串扰。 巨噬细胞和成纤维细胞。我们有三个目标来检验我们的假设。目标1确定HDAC如何 心肌梗塞后脑室的抑制影响巨噬细胞的表型、功能和由此产生的组织 微环境，以促进梗塞愈合。目标2确定纳米颗粒如何定向递送 HDAC对单核细胞和巨噬细胞的抑制影响心肌梗死后巨噬细胞转录组， 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心肌梗死后巨噬细胞与 中性粒细胞和成纤维细胞。重要的是，我们的研究将给我们重要的新的分子洞察力 I类HDAC在调节巨噬细胞极化中的作用并可能开启新的翻译 心肌梗死后VA患者的治疗方法。希望这项申请的结果将是 转化为新的和成功的临床治疗策略，以改善我们的 退伍军人。

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.