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）： 心脏病是每年超过60万人死亡（死亡率25％）的男性和女性死亡的主要原因。冠心病是心脏病最常见的类型，每年约有715,000名患者心脏病发作。由于非洲裔美国人的发生率较高，我们东南部患者人口的死亡率甚至更高。我们的VA患者反映了我们当地的人口，患心脏病的风险升高通常会出现高血压，糖尿病，肥胖或超重，吸烟和过度使用酒精。因心肌梗塞（MI）引起的LV损伤的VA患者经历心室重塑，这可能导致腔室扩张并发展为充血性心脏故障。据信单核细胞衍生的巨噬细胞在梗塞愈合的调节中起主要作用。 MI后修复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，并分泌高水平的MMP和促炎性介质。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，以帮助协调受损组织的重塑和修复。炎症单核细胞和由此产生的巨噬细胞的受控募集对于适当的愈合至关重要，但过度或长时间募集了这些炎症性单核细胞和M1巨噬细胞会导致有害的重塑和心力衰竭。最近的研究表明，将M1增加到M2极化似乎是减少炎症和改善梗塞愈合和修复的有吸引力的策略。我们的初步数据首次提供了I类HDAC将M1对M2巨噬细胞的M1极化的证据。因此，我们假设I类HDAC是巨噬细胞极化的主要调节剂，HDAC抑制剂重编程了MI心脏中M2表型的浸润单核细胞和由此产生的巨噬细胞。我们提出了三个目标来检验我们的假设。目的1）证明，抑制I类HDAC会减弱M1巨噬细胞的募集，并将M1促进M2极化，从而促进梗死愈合。目的2）确定针对I类HDAC抑制剂到炎症单核细胞的靶向输送是否会减轻MI损伤。 AIM 3）确定在动脉粥样硬化患者中常见的慢性炎症模型中，使用I类选择性HDAC抑制剂治疗是否会导致有害重塑和心室功能的保存降低。我们的方法将使我们能够直接测试靶向I类HDAC抑制剂到单核细胞和巨噬细胞是否可以覆盖急性MI心室中压倒性的炎症细胞外信号环境，以重新编程巨噬细胞表型以影响M1至M2转移。重要的是，我们的研究将使我们对I类HDAC在调节巨噬细胞极化方面的作用的重要新分子见解，并可能为治疗MI后VA后患者的治疗提供新的翻译方法。希望该应用程序的发现将转化为新的，成功的临床治疗策略，以改善我们的退伍军人损伤。