缺血预适应抑制eNOS谷胱甘肽化修饰在心脏保护中的机制研究

Ischemic preconditioning (IPC) is an important endogenous protection against myocardium ischemia reperfusion (IR), and a crucial protective mechanism of IPC is improvement of vascular function and increase of coronary blood flow (CBF). However, the specific molecular mechanism still needs further study. It is suggested endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) increased CBF in re-perfused myocardium. Recently, a new posttranslational modification--S-glutathionylation was found to make eNOS decoupling reversibly, produce less NO and damage vessel function. Our preliminary experiment suggested IPC increased eNOS de-glutathionylation to make eNOS re-coupled. So, we hypothesized IPC increase CBF to improve perfusion and protect ischemic myocardium via down-regulating eNOS S-glutathionylation; and attenuation of oxidative stress is the initial factor of eNOS S-glutathionylation reduction. In the current study, we investigate the role of eNOS S-glutathionylation in IPC protection from animal, vascular and cell aspects, and provide the new target as eNOS S-glutathionylation and evidence for therapy of ischemia reperfusion injury via a novel perspective.

缺血预适应（IPC）是心肌缺血再灌注损伤（IRI）的重要内源性保护措施，提高冠脉血流量（CBF）是IPC的重要保护机制，而其调控分子机制仍亟需深入研究。内皮型一氧化氮合酶（eNOS）产生一氧化氮（NO）是增加CBF的重要机制；最近研究发现一种新的可逆的翻译后修饰--谷胱甘肽化可导致eNOS脱偶联，NO产生减少，损伤血管功能。我们的预实验结果显示IPC可导致eNOS去谷胱甘肽化使其再偶联而恢复活性，因此我们提出如下假说：IPC通过抑制eNOS谷胱甘肽化增加CBF是其心肌保护的重要机制；IPC减轻氧化应激是抑制eNOS谷胱甘肽化的始动因素。本项目拟从动物模型、离体血管、内皮细胞三个层面上验证上述工作假说，探讨eNOS谷胱甘肽化在IPC保护心肌中的作用机制，为以eNOS谷胱甘肽化作为干预新靶点的IRI防治策略提供了实验依据。