权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium

糖尿病心肌中心肌磷脂酶和脂肪酶的调节

基本信息

批准号：
10551194
负责人：
RICHARD W GROSS
金额：
$ 77.98万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551194
关键词：
12-HETE Ablation Acceleration Acute Acyl Coenzyme A Acyltransferase Ankyrin Repeat Arrhythmia Binding Bioinformatics C-terminal Calmodulin Calpain Cardiac Myocytes Catalytic Domain Cause of Death Complex Developed Countries Development Diabetes Mellitus Dissection Eicosanoid Modulation Eicosanoids Engineering Esterification Generations Genetic Genetic Engineering Genetic Transcription Glycerol Grant Heart Heart Diseases High Fat Diet Holoenzymes Hydrolysis Hydroxyeicosatetraenoic Acids IL8 gene In Vitro Industrialization Infarction Inflammation Inflammation Mediators Inflammatory Insulin-Dependent Diabetes Mellitus Ischemia Knock-out Knockout Mice Ligands Lipase Lipids Lysophospholipase Lysophospholipids Macrophage Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathway interactions Pattern Penetration Performance Phospholipase Phospholipids Phosphorylation Physiologic pulse Plasmalogens Play Post-Translational Protein Processing Production Protein Isoforms Proteolysis Proteolytic Processing Regional Perfusion Regulation Research Resolution Risk Factors Role Signal Pathway Signal Transduction Signaling Molecule Site Societies Specificity Stable Isotope Labeling Sterility Structure Tissues Transacylase Transgenic Mice Type 2 diabetic Vertebral column Wild Type Mouse X-Ray Crystallography acylcarnitine calmodulin-dependent protein kinase II comorbidity diabetic diabetic cardiomyopathy diabetic patient experimental study hemodynamics in vivo insight interest metabolic rate mitochondrial dysfunction monocyte mouse toll-like receptor 4 nanomolar preference prevent receptor stable isotope transacylation type I and type II diabetes

项目摘要

ABSTRACT Heart disease is the most common cause of death in industrialized nations. The presence of underlying diabetes is the greatest risk factor for the progression of heart disease. During the current grant interval, we have discovered previously unknown lipid metabolic pathways and signaling molecules which lead to the generation of eicosanoid-lysophospholipids. Remarkably, the vast majority of eicosanoids in myocardium were found to be esterified to the glycerol backbone of lysophospholipids. In addition, induction of Type I diabetes in wild-type mice or ischemic damage in isolated wild-type mouse hearts resulted in dramatic increases in pro-inflammatory eicosanoid-lysophospholipids. This new class of phospholipids serve as inflammatory mediators by inducing the release of TNFa from monocytes or macrophages. Importantly, genetic ablation of iPLA2g (PNPLA8) substantially decreased the levels of eicosanoid-lysophospholipids in myocardium in the diabetic state, during myocardial ischemia and synergistically decreased their synthesis in diabetic myocardium rendered ischemic. Accordingly, we propose that iPLA2g plays a central role in the pathophysiologic development of diabetic heart disease and promotes the lethal sequelae of diabetic cardiomyopathy. In Specific Aim 1, we will utilize stable isotope labeling of isolated perfused mouse hearts from genetically engineered cardiac myocyte-specific conditional iPLA2g knockout mice we have generated. These studies will investigate the roles of iPLA2g in the metabolic flux of: 1) non-esterified and esterified eicosanoids; 2) eicosanoid-lysophospholipids; and 3) other salient oxidized phospholipids. Stable isotope pulse-chase experiments followed by penetrating bioinformatic analyses will determine rates of metabolic flux through these newly discovered pathways. Translationally, we will explore the impact of Type 2 diabetes on myocardial ischemic damage and the potential salvage of ischemic myocardium in cardiac myocyte-specific iPLA2g KO mice we engineered. Endpoints of analysis include infarct size, hemodynamic performance, and post-translational modifications of iPLA2g. In Specific Aim 2, we will utilize cardiac myocyte-specific iPLA2b KO mice we have generated to explore the role of iPLA2b in promoting myocardial ischemic damage and arrhythmias in WT vs. iPLA2b KO mice in the context of Type II diabetes. Next, we will determine the ability of iPLA2b to catalyze acyltransferase or transacylase mediated re-esterification of eicosanoid-lysophospholipids to generate oxidized phospholipids which have been implicated in damage associated molecular patterns. In Specific Aim 3, the mechanisms through which a high fat diet induces eicosanoid-lysolipid synthesis accompanied by inflammation and mitochondrial dysfunction will be studied. The roles of lysophospholipases in modulating eicosanoid-lysophospholipid levels and activation mechanisms for iPLA2g will be examined. Collectively, the proposed studies will establish the significance of iPLA2g and iPLA2b in mediating the newly identified pathways of eicosanoid-lysophospholipid synthesis and metabolism and determine their impact on diabetic cardiomyopathy and acute ischemic damage in diabetic hearts.

摘要