心脏干细胞源μ阿片受体经Caveolin-3/MG53通路介导吗啡预处理减轻慢性心衰心肌缺血后损伤的作用及机制

合并慢性心衰的患者接受心脏手术时更易发生心肌缺血后损伤，且对多种心肌保护策略不敏感。然而我们前期发现阿片预处理仍然可以减轻慢性心衰心肌缺血后损伤，该作用与心衰心脏中μ阿片受体表达上调有关，但上调的μ阿片受体源自何处及其介导阿片预处理心肌保护的信号机制仍未明确。研究表明，μ阿片受体主要在发育早期的心脏中表达，而慢性心衰心脏中心脏干细胞增殖分化形成心肌细胞明显增多，上调的μ阿片受体是否源于新分化的心肌细胞？已知阿片受体与微囊蛋白-3关系密切，而微囊蛋白-3与MG53相互作用形成复合物是心肌保护的重要分子机制。本课题拟通过梗死后慢性心衰模型，在基因、蛋白与受体层面研究慢性心衰发展的不同阶段μ阿片受体表达上调情况及其与心脏干细胞的联系；并在离体心脏及细胞水平探讨吗啡预处理经μ阿片受体调控微囊蛋白-3/MG53通路发挥心肌保护的信号机制，为临床防治慢性心衰患者在心脏手术中心肌缺血后损伤寻找新靶点。

When the patient with chronic heart failure (CHF) undergo cardiac surgery, the heart is more likely to suffer from myocardial ischemia/reperfusion injury, what’s more, large number of researches suggested that the cardioprotective effect of ischemic or pharmacological conditioning is weakened in failure heart. Our previous study has showed that morphine preconditioning protects the failing heart against ischemia/reperfusion injury, and this protection is dependent on the up-regulated cardiac μ opioid receptor. However, the issue that the origin of the increased μ opioid receptor and its role in opioids preconditioning mediated cardioprotection still remains unclear. Studies have shown that the μ opioid receptor is mainly expressed in the early stage of the formation of the heart，and the proliferation and differentiation of cardiac stem cell into cardiomyocytes is significantly increased in CHF. However, the relationship between the up-regulation of μ opioid receptor and cardiac stem cell is still dimness. It is reported that opioid receptor is closely related to Caveolin-3 whose interaction with MG53 plays a crucial role in the conditioning-induced cardioprotection. In this study, we will establish the post-infarction heart failure to observe the up-regulated expression of μ opioid receptor and its relationship with cardiac stem cell at gene, protein and receptor levels in different development stages of CHF. Furthermore, we will investigate the molecular mechanism of μ opioid receptor mediated cardioprotection by morphine preconditioning via Caveolin-3/MG53 pathway in the failing heart. The study will provide new perspectives for the treatment of myocardial ischemia/reperfusion injury in patients with CHF during cardiac surgery.