尽管心肌保护策略得到了迅速发展，如何减轻体外循环下心血管大手术因缺血/再灌注(ischemia/reperfusion, I/R)导致的心肌损伤仍是心血管麻醉医生面临的重大问题。课题组前期实验发现抗-脑源性神经营养因子前体抗体(Ab-proBDNF)可显著改善心肌I/R损伤后的心功能并减少梗死面积；并且proBDNF及其受体在I/R后心肌内表达上调，提示proBDNF可能是调控心肌I/R损伤的重要因子。本课题拟在此基础上，采用心肌细胞缺氧复氧模型和小鼠心肌I/R损伤模型，通过干预proBDNF 的表达，分别从体外和体内水平证实proBDNF促进心肌I/R损伤；进一步采用受体缺失的基因敲除小鼠模型探讨P75NTR/sortilin-JNK- caspase-3信号通路在proBDNF促进心肌I/R损伤中的作用机制。本研究将为探索I/R损伤新机制及寻找新的围术期心肌保护靶点提供线索及依据。

The cardiopulmonary bypass (CPB) is the essential method of cardiac surgery. As a result of many years of clinical and experimental research, the cardiac protection and skills of operation have been improved, but the mortality of heart operation with CPB still remains 2-5 %. The myocardial ischemia-reperfusion (I/R) injury during the CPB, could be one of the main reasons contributing to cardiac dysfunction, which is influenced by many risk factors and various molecular mechanisms. Pro-brain derived neurotrophic factor (BDNF), the precursor of BDNF, is a well characterized cytokine in the brain induced by injury. ProBDNF activates p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses. In our previous research, we found that Ab-proBDNF can significantly improve cardiac function and reduce infarct size after myocardial I/R in mouse. Further studies found that rapid upregulation of proBDNF and its receptors, P75NTR and sortilin, was observed in myocardium after reperfusion. This implied that proBDNF may be an important factor to regulate myocardial ischemia-reperfusion injury. In this study, firstly, we will isolate primary cardiomyocytes from neonatal mouse and established an in vitro model of hypoxia/reoxygenation (H/R) which resembles I/R in vivo. Together with the classic in vivo model of myocardial I/R in mouse, we will investigate the effects of proBDNF on myocardial I/R injury. Next, we will clarify the molecular mechanism of signaling pathway of P75NTR/sortilin -JNK-caspase-3 in myocardial I/R injury induced by proBDNF. Our findings will suggest an important role of cardiac proBDNF in exacerbation of myocardial I/R injury and serve as a target for pharmacotherapeutic intervention in I/R-induced myocardial injury.