Cardiovascular effects of GLP-1 in obesity/metabolic syndrome

描述（由申请人提供）：胰高血糖素样肽-1 （GLP-1）对心脏的作用最近已经被认识到，但关于这种肠促胰岛素激素的心血管生理学知之甚少。在动物模型中，GLP-1能促进心肌葡萄糖摄取，对心功能和心肌缺血损伤具有有益的保护作用。据报道，完整的GLP-1通过经典的GLP-1受体和降解产物GLP-1起作用，而GLP-1似乎独立于GLP-1受体起作用。在肥胖和糖尿病对心肌GLP-1反应影响的研究中，我们首次发现了在猪肥胖代谢综合征（MetS）和人类2型糖尿病的情况下心肌GLP-1反应受损的证据。基于我们的初步研究结果，我们建议检验肥胖/MetS通过改变GLP-1信号传导和/或燃料运输调节参数来减弱GLP-1的心脏代谢作用的中心假设。为了实现我们的目标，我们将研究以下一组特定目的：目的1将确定GLP-1在体内对瘦猪和肥胖/MetS猪的心肌影响，这些猪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。这些研究包括三重示踪PET方法来测量基础和GLP-1刺激的心肌灌注、总氧化率和底物利用率，以及定量测量GLP-1对心功能、冠状动脉血流量和底物代谢的影响，在运动诱导的心肌代谢增加中，有意识的，仪器猪。目的2将剖析肥胖/MetS患者心肌GLP-1反应受损的分子机制。我们建议量化瘦猪与肥胖/MetS猪的冠状动脉和心肌GLP-1受体表达，并评估GLP-1和GLP-1（9-36）对GLP-1关键信号效应物（如cAMP、PKA、p38 MAPK）活性和心肌葡萄糖和脂肪酸转运体（如GLUT4、FAT/CD36）调节的影响。目的3将研究GLP-1在缺血/再灌注损伤后肥胖/MetS心脏中的心脏保护作用。我们拟量化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。GLP-1对缺血和非缺血心肌关键信号转导、心肌细胞损伤标志物、后适应保护通路激活和心肌损伤反应的影响也将被确定。来自这些综合/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，这将显著推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大大提高基于GLP-1的治疗对肥胖相关心血管疾病患者的心脏保护功效。

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.