Cardiovascular effects of GLP-1 in obesity/metabolic syndrome

描述(申请人提供)：最近已认识到胰高血糖素样肽-1(GLP-1)对心脏的作用，但对这种胰岛素激素的心血管生理学知之甚少。GLP-1可促进心肌葡萄糖摄取，对动物模型心功能和心肌缺血损伤有保护作用。据报道，完整的GLP-1通过经典的GLP-1受体发挥作用，降解产物GLP-1(9-36)似乎独立于GLP-1受体发挥作用。在肥胖和糖尿病对心肌GLP-1反应影响的研究中，我们首次提出了在猪肥胖代谢综合征(METS)和人类2型糖尿病的背景下心肌GLP-1反应受损的证据。根据我们的初步发现，我们建议检验肥胖/蛋氨酸通过改变GLP-1信号和/或燃料运输调节参数来减弱GLP-1的心脏代谢效应的中心假设。为了实现我们的目标，我们将研究以下一组特定目标：目标1将确定GLP-1在体内对具有这种综合征关键临床特征的瘦肉型和肥胖/Mets Ossabaw猪的心肌影响，这些症状包括肥胖、胰岛素抵抗/糖耐量受损、血脂异常和高血压。这些研究涉及三重示踪PET方法，以测量基础和GLP-1刺激的心肌灌注、总氧化率和底物利用率，以及量化GLP-1在运动诱导清醒的仪器化猪心肌代谢增加期间对心功能、冠脉血流量和底物代谢的影响。目的2将剖析肥胖/蛋氨酸引起的心肌GLP-1反应受损的分子机制。我们建议量化GLP-1受体在冠状动脉和心肌的表达，并评估GLP-1和GLP-1(9-36)对瘦肉型和肥胖型/蛋氨酸猪的关键GLP-1信号效应因子(如cAMP、PKA、p38MAPK)的活性以及对心肌葡萄糖和脂肪酸转运体(如GLUT4、FAT/CD36)的调节作用。目的研究GLP-1对肥胖/蛋氨酸心脏缺血再灌注损伤的保护作用。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、收缩功能和梗塞范围的影响。GLP-1对缺血和非缺血心肌的关键信号转导、心肌细胞损伤标志物、后处理保护通路的激活和心肌损伤反应的影响也将被确定。这些综合/翻译研究的数据将为GLP-1的心血管作用提供新的机制洞察力，这将极大地促进我们对这种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目标或策略，可以显著提高肥胖相关心血管疾病患者基于GLP-1的治疗的心脏保护效果。

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.