Regulatroy Role of HDAC in Post-MI Ventricular Remodeling

描述(由申请人提供)： 心脏病是男性和女性的主要死亡原因，每年有超过60万人死亡(占死亡率的25%)。冠心病是最常见的心脏病类型，每年约有71.5万名患者心脏病发作。东南部患者的死亡率甚至更高，非洲裔美国人的死亡率更高。我们的退伍军人管理局患者反映出我们当地人群患心脏病的风险增加，通常表现为高血压、糖尿病、肥胖或超重、吸烟和过度饮酒。因心肌梗死(MI)导致左室损伤的VA患者会经历心室重构，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在脑梗塞愈合的调节中发挥重要作用。心肌梗死后修复由炎性M1巨噬细胞介导的I期双相过程组成，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，帮助协调受损组织的重塑和修复。炎性单核细胞和由此产生的巨噬细胞的受控募集对于正常愈合是必不可少的，但这些炎性单核细胞和M1巨噬细胞的过度或长期募集会导致有害的重塑和心力衰竭。最近的研究表明，增加M1到M2的极化似乎是一种有吸引力的策略，可以减轻炎症，改善心肌梗死的愈合和修复。我们的初步数据首次提供了I类HDAC调节MI后心脏巨噬细胞M1到M2极化的证据。因此，我们假设I类HDAC作为巨噬细胞极化的主要调节器，并且HDAC抑制剂将渗透的单核细胞和由此产生的巨噬细胞重新编程为MI后心脏的M2表型。我们提出了三个目标来检验我们的假设。目的1)证实抑制I类HDAC可减弱M1巨噬细胞募集，促进M1到M2极化，从而促进梗塞愈合。目的2)确定靶向炎性单核细胞递送I类HDAC抑制剂是否能减轻心肌梗死损伤。目的3)确定在动脉粥样硬化患者常见的慢性炎症小鼠模型中，使用I类选择性HDAC抑制剂治疗是否能减少有害重塑和保护心功能。我们的方法将使我们能够直接测试靶向向单核细胞和巨噬细胞递送I类HDAC抑制剂是否可以覆盖急性MI脑室中压倒性的炎性细胞外信号环境，以重新编程巨噬细胞表型，影响M1向M2的转变。重要的是，我们的研究将为我们提供重要的新的分子见解，了解I类HDAC在调节巨噬细胞极化中的作用，并可能打开一种新的翻译方法来治疗MI后VA患者。希望这一应用的结果将转化为新的和成功的临床治疗策略，以改善我们退伍军人的心肌梗死后损伤。

DESCRIPTION (provided by applicant): 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 progress to congestive heart fail-ure. 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. Recent studies have demonstrated that increasing the M1 to M2 polarization appears to be an attractive strategy for decreasing inflammation and improvement of infarct healing and repair. Our preliminary data provide evidence for the first time that class I HDACs regulate M1 to M2 polarization of macrophages of the post-MI heart. Therefore, we hypothesize that class I HDACs serve as a master regulator of macrophage polarization and HDAC inhibitors reprogram the infiltrating monocytes and resulting macrophages toward the M2 phenotype in the post-MI heart. We have proposed Three Aims to test our hypothesis. Aim 1) Demonstrate that inhibition of class I HDACs attenuates M1 macrophage recruitment and promotes M1 to M2 polarization, which fosters infarct healing. Aim 2) Determine if targeted delivery of a class I HDAC inhibitor to inflammatory monocytes attenuates MI injury. Aim 3) Determine if treatment with a class I selective HDAC inhibitor in a murine model of chronic inflammation commonly seen in patients with atherosclerosis, results in reduced deleterious remodeling and preservation of ventricular function. Our approach will allow us to directly test whether targeted delivery of class I HDAC inhibitors to monocytes and macrophages can override the overwhelming inflammatory extracellular signaling milieu in the acute MI ventricle to reprogram macrophage phenotype to influence M1 to M2 transition. 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.