ALTERED PPARx SIGNALING IN THE ISCHEMIC DIABETIC HEART

该SCCOR项目将重点研究糖尿病患者的心肌脂代谢异常。糖尿病心脏中脂肪酸利用率的长期增加易导致与氧气消耗增加和细胞内脂肪堆积相关的心脏毒性效应(“脂毒性”)。在心肌缺血的背景下，线粒体脂肪酸氧化(FAO)的高比率可能导致心肌细胞损伤和死亡的增加。最近，我们发现核受体，过氧化物酶体增殖物激活受体α或PPARα，驱动糖尿病心脏中脂肪利用的增加。该项目将检验这样一种假设，即心脏PPARpha途径的慢性激活引起的代谢紊乱是糖尿病患者急性冠脉缺血后心力衰竭和死亡的主要决定因素。我们已经开发了小鼠模型来复制糖尿病心脏的脂代谢紊乱。心脏特异过表达PPARpha(MHC-PPAR)的转基因小鼠表现出与糖尿病心脏明显相似的代谢表型。第二种模型涉及心脏特有的脂蛋白脂肪酶的过度表达，以增加脂肪酸向心脏的输送。我们将研究小鼠模型对缺血侮辱的反应。首先，将使用小鼠模型来评估对心肌梗死和缺血/再灌注的代谢和功能反应。其次，我们将通过评估饮食脂肪含量的影响，以及利用LPL转基因和“基因敲除”增加或减少脂蛋白衍生脂肪酸的输送的影响，来评估心脏脂毒性在糖尿病心肌病表型中的贡献作用。第三，我们将评估针对PPAR途径及其靶基因的药物的影响。最后，我们将对PPARpha复合体基因中常见的单核苷酸多态(SNPs)的影响进行功能研究，以补充项目4和项目5中计划的人群研究的结果。该项目的长期目标是与项目2-5合作，识别新的脂类生化、代谢成像和遗传决定因素，预测有急性冠脉缺血性损伤风险的个体糖尿病患者的预后。

This SCCOR project will focus on abnormalities of myocardial lipid metabolism in the diabetic patient. Chronically increased rates of fatty acid utilization in the diabetic heart predispose to cardiotoxic effects related to increased oxygen consumption and accumulation of intracellular fipids ("lipotoxicity"). In the setting of myocardial ischemia, high rates of mitochondrial fatty acid oxidation (FAO) may lead to increased myocyte injury and death. Recently, we have found that the nuclear receptor, peroxisome proliferator-activated receptor alpha or PPARalpha, drives increased fatty utilization in the diabetic heart. This project will test the hypothesis that metabolic derangements due to chronic activation of the cardiac PPARalpha pathway are a major determinant of heart failure and death in diabetics following acute coronary isehemia insult. We have developed mouse models to reproduce the lipid metabolic derangements of the diabetic heart. Transgenic mice with cardiac-specific overexpression of PPARalpha (MHC-PPAR) exhibits a metabolic phenotype remarkedly similar to the diabetic heart. A second model involves cardiac-specific overexpression of lipoprotein lipase to increase delivery of fatty acids to the heart. We will study the response of the mouse models to ischemic insult. First, the mouse models will be used to evaluate the metabolic and functional response to myocardial infarction and ischemia/reperfusion. Second, we will evaluate the contributory role of cardiac lipotoxicity in the diabetic cardiomyopathic phenotype by evaluating the influence of dietary fat content and the effects of increased or decreased delivery of lipoprotein-derived fatty acid using LPL transgenics and "knockouts", respectively. Third, we will evaluate the influence of pharmacologic agents targeted at the PPAR pathway and its target genes. Lastly, we will perform fimctional studies of the effects of common single nucleotide polymorphisms (SNPs) within genes of the PPARalpha complex to compliment the results of population studies planned in Projects 4 and 5. The long-term goal of this project, in collaboration with Projects 2-5, is to identify novel lipid biochemical, metabolic imaging, and genetic determinants predictive of outcome in an individual diabetic patient at risk for acute cornary ischemic insult.