Regulatroy 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: 8975085
• 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 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975085
• 关键词: Acetylation; Acute myocardial infarction; Affect; African American; Aftercare; Alcohol consumption; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Area; Atherosclerosis; Attenuated; Biological Preservation; Blood; Cardiac; Cause of Death; Cessation of life; Chromatin Structure; Chronic; Clinical Treatment; Complex; Congestive; Congestive Heart Failure; Coronary Arteriosclerosis; Coronary heart disease; Cytolysis; Data; Death Rate; Development; Diabetes Mellitus; EFRAC; Endothelial Cells; Enzyme Inhibition; Enzymes; Fibrosis; Fostering; Gene Expression; Genes; Genetic Programming; Healed; Health; Heart; Heart Diseases; Heart failure; Histone Deacetylase; Histones; Hour; Hypertension; Impaired wound healing; In Vitro; Infarction; Inflammation; Inflammatory; Injury; Lead; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Modeling; Molecular; Monocytosis; Mus; Myocardial Infarction; Myocardium; Myofibroblast; Obesity; Overweight; Patients; Peptide Hydrolases; Phase; Phenotype; Play; Population; Pre-Clinical Model; Process; Recruitment Activity; Regulation; Rheumatoid Arthritis; Role; Septic Shock; Signal Transduction; Smoking; Stem cells; Stimulus; Testing; Therapeutic; Time; Tissues; Transferase; Translating; United States; Ventricular Function; Ventricular Remodeling; Veterans; Woman; cytokine; extracellular; healing; heart disease risk; in vivo; inhibitor/antagonist; insight; macrophage; men; monocyte; mortality; mouse model; nanoparticle; neutrophil; patient population; prevent; repaired; response; targeted delivery; tissue regeneration; transcription factor; translational approach; treatment strategy

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.

描述（由申请人提供）： 心脏病是男性和女性的主要死因，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715，000名患者患有心脏病发作。我们东南部病人的死亡率甚至更高，非洲裔美国人的死亡率更高。我们的VA患者反映了我们当地心脏病风险升高的人群，通常表现为高血压、糖尿病、肥胖或超重、吸烟和过度饮酒。由于心肌梗死（MI）而导致LV损伤的VA患者经历心室重构，这可导致腔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在梗死愈合的调节中起主要作用。MI后修复由双相过程组成，其中I相由炎性M1巨噬细胞介导，所述炎性M1巨噬细胞是吞噬细胞，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，并与肌成纤维细胞、内皮细胞、实质细胞和局部祖细胞沟通，以帮助协调受损组织的重塑和修复。炎性单核细胞和产生的巨噬细胞的受控募集对于适当愈合是必不可少的，但是这些炎性单核细胞和M1巨噬细胞的过度或长期募集导致有害的重塑和心力衰竭。最近的研究表明，增加M1至M2极化似乎是减少炎症和改善梗死愈合和修复的一种有吸引力的策略。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至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剂，HDAC抑制剂将浸润的单核细胞和所得巨噬细胞重编程为MI后心脏中的M2表型。我们提出了三个目标来检验我们的假设。目的1）证明I类HDAC的抑制减弱M1巨噬细胞募集并促进M1至M2极化，这促进梗死愈合。目的2）确定将I类HDAC抑制剂靶向递送至炎性单核细胞是否减弱MI损伤。目的3）确定在动脉粥样硬化患者中常见的慢性炎症的鼠模型中用I类选择性HDAC抑制剂治疗是否导致有害的重构减少和心室功能的保留。我们的方法将使我们能够直接测试I类HDAC抑制剂靶向递送至单核细胞和巨噬细胞是否可以覆盖急性MI心室中压倒性的炎性细胞外信号传导环境，以重新编程巨噬细胞表型，从而影响M1至M2的转变。重要的是，我们的研究将为我们提供关于I类HDAC在调节巨噬细胞极化中的作用的重要新分子见解，并可能为治疗MI后VA患者开辟一种新的转化方法。希望这项应用的结果将转化为新的和成功的临床治疗策略，以改善我们的退伍军人心肌梗死后损伤。