神经生长因子在糖尿病心肌缺血后适应保护效应中的作用

Ischemic postconditioning (iPoCo) is an important endogenous mechanism of myocardial protection against ischemia/reperfusion (IR) injury, which is inhibited by diabetic millitus (DM), and the specific mechanism is still unclear. Nerve growth factor (NGF) is a critical neurotrophic factor, and the decline of endogenous NGF is involved in diabetic cardiac neuropathy. We have demonstrated a significant increase of NGF in ischemic myocardium. Accordingly, we inferred that " the inherent cardioprotection against IR is greatly weakened due to diabetic nerve damage or neurological disorder, which could be improved by administration of exogenous NGF, and the protective effect by iPoCo in DM would be restored.".In this study, we intend to observe the modulation of endogenous NGF on cardiac sympathetic and sensory nerve functions during IR; the relationship between NGF and neurobiology changes in DM heart; focusing on whether NGF gene transduction by adeno-associated virus vector could relieve diabetic myocardial IR injury, and regain the missing protective effect of iPoCo, and further explore the targets and signaling molecules of NGF action..Here, we investigate the role and mechanism of NGF in iPoCo -mediated cardioprotection from the point of DM neuropathology for the first time, and try to come up with new perspectives on prevention and treatment of IR injury in DM myocardium.

缺血后适应（iPoCo）是缺血再灌注（IR）心肌保护的重要内源性机制，但糖尿病（DM）心脏对iPoCo减敏，具体机制不清。神经生长因子（NGF）具有重要的神经调控作用，DM神经病变累及心脏神经并抑制内源性NGF表达。我们已证实，缺血心肌NGF显著增加。据此推测“DM心肌缺血后神经调节失衡削弱了心脏固有保护机制，外源性NGF可通过改善神经功能恢复DM心肌iPoCo保护作用”。课题首先观察内源性NGF对IR心脏交感和感觉神经功能的调制作用；DM大鼠心脏神经生物学改变与NGF的相关性；重点关注在DM心脏神经受损基础上，通过腺相关病毒载体导入NGF基因能否减轻心肌IR损伤，逆转DM状态下缺失的iPoCo保护效应，并探索NGF作用的效应靶点和信号级联。首次在整体系统、器官、细胞、离子通道和分子水平，从神经病理学角度探讨NGF在DM心肌iPoCo保护中的作用及机制，为DM心肌IR损伤的防治提供新思路。