运动通过改善心肌梗死后下丘脑室旁核氧化应激对心功能的保护效应及机制探讨

Myocardial infarction (MI) is one of the most fateful diseases. MI is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in MI. PVN neurons are chronically activated after MI, and that this parallels the sustained elevations in sympathetic outflow during MI. Substantial evidence implicates reactive oxygen species as key signaling molecules in PVN in maintaining cardiovascular homeostasis. MI causes a robust increase in NOX4-mediated superoxide radical formation in PVN. New researches indicate that targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI. And exercise is one of the clinical interventions for the prevention and treatment of MI. The antioxidant effects of exercise following MI have been well recognized. So the purpose of this project is to study the protective effect of aerobic interval training on MI by oxidative stress reduction in the paraventricular nucleus. We investigated whether aerobic interval training was able to inhibit sympathetic nerve sprouting, restore β-ARs balance, improve cardiac function by oxidative stress reduction in the PVN after MI, and explore the possible mechanism by the methods of hemodynamics, immunohistochemistry, immunofluorescence staining, western blot and RT-PCR separately. This study wants to provide the evidence for protective effects of aerobic interval training on cardiac function and cardiac rehabilitation in MI rats.

心肌梗死（MI）是危害人类健康的主要杀手之一。近年来心血管中枢在MI中的作用研究已经成为关注热点。其中下丘脑室旁核（PVN）是重要的心血管中枢和交感神经活动整合区。MI后PVN氧化应激水平增高导致心脏交感神经过度激活，加重MI。而以PVN为靶点抑制中枢氧化应激，可能成为治疗MI的手段之一。本项目拟对MI大鼠进行间歇有氧运动(AIT)，通过PVN插管术注射药物，采用免疫荧光，RT-PCR，Western blot， ELISA，心功能测试等方法，探讨NADPH 氧化酶是否在AIT降低MI后PVN氧化应激水平中发挥作用及其分子机制。确定MI后PVN氧化应激与心脏交感神经重构，β受体脱敏，均衡性的关系；阐明运动降低MI后PVN应激水平对心功能的提升，是否通过抑制心脏交感神经重构，改善β受体均衡性及其分子机制。为改善缺血心肌功能和心脏康复提供理论依据，为安全有效治疗MI提供方法学参考。

通过构建心肌梗死大鼠模型，进行四周有氧递增运动干预，采用侧脑室插管术注射药物，免疫荧光，免疫组化，qRT-PCR，Western blot， ELISA，心功能测试等方法，测试大鼠心电图，血流动力学指标。心脏TTC染色观察梗死面积，Masson染色测定心肌胶原容积百分比(CVF)。检测心梗大鼠心交感神经重构相关指标(TH、GAP-43、NGF、TrkA、p75NTR)、心脏β-AR各亚型(β1-AR、β2-AR、β3-AR)表达、β3-AR下游通路(Akt、p-Akt、NOS3、p-NOS3、NOS1和p-NOS1)、中枢PVN区氧化应激水平指标(MDA、SOD、T-AOC、NADPH 氧化酶亚型Nox1、Nox2、Nox4表达等)。并通过建立中枢给药引起的PVN区氧化应激降低模型，观察其对心梗大鼠脏交感神经结构重塑的影响。确定中枢氧化应激与心交感神经重构的关系。.结果发现运动干预可下调心脏NGF-TrkA通路，增加p75NTR表达，抑制心梗后心交感神经重构。运动可恢复心梗心脏β-AR均衡性，上调β3-AR及其下游NOS3和Akt-NOS1通路，提升心梗大鼠心功能。运动干预可降低心梗大鼠PVN区NADPH 氧化酶来源的氧化应激水平，减弱PVN区神经元活动，其与中枢给药效果一致。心梗后PVN区氧化应激与心交感神经重构存在关系。运动降低PVN区氧化应激与改善心交感神经重构关系密切。运动可能通过降低PVN区氧化应激，改善心脏交感神经重构及β-AR均衡性，保护心梗大鼠心功能。.项目资助发表SCI论文1篇，CSSCI论文3篇，另有2篇论文正在投稿修改。