Cardiac protective mechanisms of melanocortin system activation

项目总结/摘要 每年有超过150万美国人患有心肌梗死（MI），其中约25%的患者 发生严重的心功能不全，包括充血性心力衰竭（HF），5年死亡率较高 率~ 50%。目前MI后的治疗在减轻心功能不全和减缓心功能不全方面的成功有限。 HF进展。因此，迫切需要新的、更有效的治疗方法，其保护心脏，改善心功能， 其功能和减缓/停止心功能障碍进展。我们最近证明， 脑瘦素-黑皮质素系统途径大大改善心肌细胞能量代谢和收缩力， 保护心脏功能，并防止左前叶结扎诱导的MI后HF的进展 冠状动脉降支我们观察到脑室（ICV）输注瘦素4周， 低剂量不改变血液瘦素浓度，恢复射血分数，心输出量，左心室（LV） 肌肉拉伤和左心房/主动脉直径比几乎完全恢复到正常基线值，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， 也有明显改善。我们还观察到这些心脏保护作用在黑皮质素4中不存在， 受体（MC 4 R）缺陷大鼠和脑MC 4 R的激活使用合成激动剂注入到 脑室以类似的方式保护心脏免受MI后进行性心功能不全的影响 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-MC 4 R通路的激活， 增加沉默调节蛋白-3（SIRT 3）表达，线粒体生物发生和底物氧化（即，葡萄糖和脂肪 酸氧化），并改善LV非梗死区域的心肌细胞收缩性，包括 风险，但仍然可行。这个提议的中心假设是大脑黑皮质素系统的激活 改善心脏功能，预防MI后HF进展，增加心肌 线粒体生物合成和SIRT 3水平，增强底物氧化，并提高能量 在心脏的健康部分中的生产和心肌细胞收缩性。我们还建议， 黑皮质素系统对心脏的有益作用需要PVN中的MC 4 R活化和/或 DMV/NTS/IML，以及MC 4 R激动剂，其穿过血脑屏障（例如，塞替米拉诺肽）并且可以 即使在肥胖的情况下，全身给药也能有效地提供心脏保护。 我们将使用最先进的慢性体内协议与高分辨率超声成像技术 基因工程动物心脏功能（包括4D应变超声心动图成像技术） 与离体和体外制备物组合的模型用于详细测量心肌功能， 形态、能量代谢和收缩性来检验我们的假设。这项研究的结果可以 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MC 4 R提供新的靶点 目前用于治疗人类中罕见形式的遗传性肥胖症的激动剂。

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.