Cardiac protective mechanisms of melanocortin system activation

项目摘要/摘要 每年有超过150万美国人患有心肌梗塞，其中约25%的患者患有心肌梗塞 发展为严重的心脏功能障碍，包括充血性心力衰竭(HF)，其5年死亡率很高 ~50%的比率。目前心肌梗塞后的治疗在减轻心功能障碍和减缓心功能障碍方面的成功有限。 心衰进展。因此，迫切需要新的、更有效的治疗方法来保护心脏、改善 它的功能，以及心功能障碍的缓慢/停止进展。我们最近证明了激活 脑瘦素-黑素皮质素系统通路显著改善心肌细胞能量代谢和收缩能力， 保护心功能，防止左前壁结扎引起的心梗后心力衰竭的进展 冠状动脉下行。我们观察到脑室(Icv)注射瘦素4周后， 低剂量不改变血瘦素浓度，恢复射血分数，心输出量，左心室(LV) 肌肉应变和左房/主动脉直径比几乎一直回到正常基线值，以及 初步数据表明，心脏功能的其他指标，如+dp/dtmax和运动能力 也有明显的改善。我们还观察到，黑素皮质素4没有这些心脏保护作用。 受体(MC4R)缺陷大鼠和脑内注入合成激动剂对MC4R的激活 脑室以类似的方式保护心脏免受心肌梗死后进行性心功能障碍的影响 与瘦素治疗相比。我们的初步数据还表明，中枢神经系统瘦素-MC4R通路的激活 增加sirtuin-3(SIRT3)的表达、线粒体的生物合成和底物氧化(即葡萄糖和脂肪 酸性氧化)，并改善左室非梗死区的心肌细胞收缩能力，包括 有风险，但仍有生存能力。这一提议的中心假设是大脑黑素皮质素系统的激活 改善心功能，防止心梗后心衰进展，增加心肌 线粒体生物发生和SIRT3水平，增强底物氧化，提高能量 心脏健康部位的产量和心肌细胞的收缩能力。我们还建议，这些 黑素皮质素系统对心脏的有益作用需要在室旁核和/或激活MC4R DMV/NTS/IML，以及穿过血脑屏障的MC4R激动剂(如setmelanoide)，并可以 即使在肥胖的情况下，系统地给予也将有效地提供心脏保护。 我们将使用最先进的慢性活体方案和高分辨率超声技术进行成像 基因工程动物的心功能(包括4D-应变超声心动图成像技术) 结合体外和体外准备的详细测量心肌功能的模型， 形态、能量代谢和收缩能力来检验我们的假说。这项研究的结果可能是 为心肌梗死和心力衰竭的治疗提供了新的、更有效的方法，并将为MC4R提供新的靶点 激动剂目前正被用于治疗人类罕见形式的遗传性肥胖。

PROJECT SUMMARY/ABSTRACT Over 1.5 million Americans suffer from myocardial infarction (MI) each year, and about 25% of these patients develop severe cardiac dysfunction including congestive heart failure (HF), which has a high 5-year mortality rate of ~50%. Current therapies following MI have limited success in attenuating cardiac dysfunction and slowing HF progression. Thus, there is a critical need for novel, more effective therapies that protect the heart, improve its function, and slow/halt progression of cardiac dysfunction. We recently demonstrated that activation of the brain leptin-melanocortin system pathway greatly improves cardiomyocyte energy metabolism and contractility, preserves cardiac function, and prevents progression of HF following MI induced by ligation of the left anterior descending coronary artery. We observed that intracerebroventricular (ICV) infusion of leptin for 4 weeks, at a low dose that did not alter blood leptin concentration, restored ejection fraction, cardiac output, left ventricle (LV) muscle strain and left atrium/aorta diameter ratio almost all the way back to normal baseline values, and preliminary data suggest that other measures of cardiac function such as +dP/dtmax and exercise capacity were also markedly improved. We also observed that these cardiac protective effects are absent in melanocortin 4 receptor (MC4R) deficient rats and that activation of brain MC4R using synthetic agonists infused into the cerebral ventricles protected the heart against progressive cardiac dysfunction after MI in a similar fashion compared to leptin treatment. Our preliminary data also indicate that activation of the CNS leptin-MC4R pathway increases sirtuin-3 (SIRT3) expression, mitochondrial biogenesis and substrate oxidation (i.e., glucose and fatty acid oxidation), and improves cardiomyocyte contractility in non-infarcted regions of the LV, including areas at risk but still viable. The central hypothesis of this proposal is that activation of the brain melanocortin system improves cardiac function and prevents progression of HF after MI, increases myocardium mitochondrial biogenesis and SIRT3 levels, enhances substrate oxidation, and improves energy production and cardiomyocyte contractility in healthy portions of the heart. We also propose that these beneficial effects of the melanocortin system on the heart require MC4R activation in PVN and/or DMV/NTS/IML, and that MC4R agonists that cross the blood-brain barrier (e.g. setmelanotide) and can be administered systemically will be effective to provide cardioprotective even in the setting of obesity. We will use state-of-the-art chronic in vivo protocols with high-resolution ultrasound techniques for imaging cardiac function (including 4D-strain echocardiographic imaging technology) in genetically engineered animal models combined with ex vivo and in vitro preparations for detailed measurements of cardiac muscle function, morphology, energy metabolism and contractility to test our hypotheses. The outcomes from this study could lead to novel and more effective therapeutic approaches for MI and HF, and will provide a new target for MC4R agonists which are currently being used to treat rare forms of genetic obesity in humans.