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: 10265359
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265359
• 关键词: Acetylation; Affect; African American; 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; Image; Infarction; Inflammation; Inflammatory; Injury; Interleukin-10; Interleukin-4; Kinetics; Lead; Lipids; Maps; Mass Spectrum Analysis; 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; 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.

心脏病是男女死亡的主要原因，每年有60多万人死亡