ALTERED PPARx SIGNALING IN THE ISCHEMIC DIABETIC HEART

该SCCOR项目将关注糖尿病患者的心肌脂质代谢异常。糖尿病心脏中脂肪酸利用率的慢性增加易发生与氧消耗增加和细胞内脂质积累相关的心脏毒性作用（“脂毒性”）。在心肌缺血的情况下，线粒体脂肪酸氧化（FAO）的高速率可导致肌细胞损伤和死亡增加。最近，我们发现核受体，过氧化物酶体增殖物激活受体α或PPARalpha，驱动糖尿病心脏中脂肪利用的增加。本项目将检验以下假设：心脏PPARalpha通路慢性激活导致的代谢紊乱是糖尿病患者急性冠状动脉缺血损伤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质代谢紊乱。心脏特异性过表达PPARalpha（MHC-PPAR）的转基因小鼠表现出与糖尿病心脏显著相似的代谢表型。第二种模型涉及心脏特异性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性损伤的反应。首先，小鼠模型将用于评价对心肌梗死和缺血/再灌注的代谢和功能反应。其次，我们将评估心脏脂毒性在糖尿病心肌病表型中的贡献作用，通过评估膳食脂肪含量的影响和使用LPL转基因和“敲除”分别增加或减少脂蛋白衍生的脂肪酸的递送的影响。第三，我们将评估靶向PPAR通路及其靶基因的药理学药物的影响。最后，我们将对PPARalpha复合物基因内常见单核苷酸多态性（SNP）的影响进行功能研究，以补充项目4和5中计划的人群研究结果。该项目的长期目标是与项目2-5合作，确定新的脂质生化，代谢成像和遗传决定因素，预测个体糖尿病患者急性冠状动脉缺血性损伤的风险。

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.