Cardiovascular effects of GLP-1 in obesity/metabolic syndrome

描述（由申请方提供）：胰高血糖素样肽-1（GLP-1）对心脏的作用最近已被认识，但关于这种肠促胰岛素激素的心血管生理学知之甚少。GLP-1可驱动心肌葡萄糖摄取，在动物模型中对心功能和心肌缺血损伤具有有益作用。已报告了完整GLP-1（通过经典GLP-1受体发挥作用）和降解产物GLP-1（9-36）（似乎不依赖于GLP-1受体发挥作用）的这些效应。在肥胖和糖尿病对心肌GLP-1反应影响的研究中，我们首次获得了猪肥胖代谢综合征（MetS）和人类2型糖尿病背景下心肌GLP-1反应受损的证据。基于我们的初步研究结果，我们建议检查的中心假设，肥胖/代谢综合征减弱心脏代谢的GLP-1的影响，通过改变GLP-1信号和/或燃料运输调节的参数。为了实现我们的目标，我们将检查以下一组特定目的：目的1将确定GLP-1在具有该综合征的关键临床特征（包括肥胖、胰岛素抵抗/糖耐量受损、血脂异常和高血压）的瘦型和肥胖/MetS Ossabaw猪中的体内心肌效应。这些研究涉及三重示踪PET方法，以测量清醒、仪器化猪运动诱导心肌代谢增加期间的基础和GLP-1刺激心肌灌注、总氧化率和底物利用率，以及定量GLP-1对心脏功能、冠状动脉血流量和底物代谢的影响。目的2将剖析肥胖/代谢综合征心肌GLP-1反应受损的分子机制。我们建议在瘦猪与肥胖/MetS猪中定量冠状动脉和心肌GLP-1受体表达，并评估GLP-1和GLP-1（9-36）对关键GLP-1信号效应物（例如cAMP、PKA、p38 MAPK）活性以及心肌葡萄糖和脂肪酸转运蛋白（例如GLUT 4、FAT/CD 36）调节的影响。目的3将检测GLP-1在肥胖/MetS心脏缺血/再灌注损伤后的心脏保护作用。我们建议量化GLP-1和GLP-1（9-36）对心肌灌注、底物和氧化代谢、收缩功能和梗死面积的影响。还将确定GLP-1对缺血和非缺血心肌中关键信号转导、肌细胞损伤标志物以及后调节保护途径和心肌损伤反应的激活的影响。来自这些整合/转化研究的数据将为GLP-1的心血管作用提供新的机制见解，这将显著促进我们对这种肠促胰岛素激素的心脏保护作用的理解。此外，这些研究将加速发现新的治疗靶点或策略，这些靶点或策略可以显著改善基于GLP-1的治疗在肥胖相关心血管疾病患者中的心脏保护功效。

DESCRIPTION (provided by applicant): Effects of glucagon-like peptide-1 (GLP-1) on the heart have been recently recognized, but little is known regarding the cardiovascular physiology of this incretin hormone. GLP-1 can drive myocardial glucose uptake, and has beneficial effects on cardiac function and protection against myocardial ischemic injury in animal models. These effects have been reported for intact GLP-1, acting via the classical GLP-1 receptor, and the degradation product GLP-1 (9-36), which appears to act independent of the GLP-1 receptor. In studies of the effects of obesity and diabetes on myocardial GLP-1 responses, we have produced the first evidence for impaired myocardial GLP-1 responses in the setting of the obese-metabolic syndrome (MetS) in swine and type 2 diabetes mellitus in humans. Based on our preliminary findings we propose to examine the central hypothesis that obesity/MetS attenuates the cardio-metabolic effects of GLP-1 via alterations in parameters of GLP-1 signaling and/or fuel transport regulation. To accomplish our goal, we will examine the following set of Specific Aims: Aim 1 will determine the myocardial effects of GLP-1 in vivo in lean and obese/MetS Ossabaw swine that possess key clinical features of this syndrome, including obesity, insulin resistance/impaired glucose tolerance, dyslipidemia, and hypertension. These studies involve triple tracer PET approaches to measure basal and GLP-1 stimulated myocardial perfusion, total oxidation rate, and substrate utilization rates as well as quantificatin of the effects of GLP-1 on cardiac function, coronary blood flow and substrate metabolism during exercise-induced increases in myocardial metabolism in conscious, instrumented swine. Aim 2 will dissect molecular mechanisms of the impaired myocardial GLP-1 responses in obesity/MetS. We propose to quantify coronary and myocardial GLP-1 receptor expression and assess the effects of GLP-1 and GLP-1(9-36) on the activity of key GLP-1 signaling effectors (e.g. cAMP, PKA, p38 MAPK) and the regulation of myocardial glucose and fatty acid transporters (e.g. GLUT4, FAT/CD36) in lean vs. obese/MetS swine. Aim 3 will examine the cardioprotective effects of GLP-1 in obese/MetS heart following ischemia/reperfusion injury. We propose to quantify the effects of GLP-1 and GLP-1(9-36) on myocardial perfusion, substrate and oxidative metabolism, contractile function and infarct size. Effects of GLP-1 on key signal transduction, markers of myocellular injury, and activation of post-conditioning protective pathways and myocardial injury responses in ischemic and non-ischemic myocardium will also be determined. Data from these integrative/translational studies will provide novel mechanistic insight into the cardiovascular actions of GLP-1 that will significantly advance our understanding of the cardioprotective actions of this incretin hormone. Further, these studies will accelerate discovery of new therapeutic targets or strategies that could substantially improve the cardioprotective efficacy of GLP-1 based therapies in patients with obesity-related cardiovascular disease.