缺血后处理心肌保护中线粒体机制的研究进展

Involvement of mitochondrial mechanisms in myocardial protection by ischemic postconditioning

背景心肌缺血/再灌注损伤（myocardial ischemia/reperfusion injury, MI/RI）严重威胁着心血管疾病患者生命安全，合并糖尿病患者病死率明显增加。缺血后处理（ischemic postconditioning, IPO）作为一种有效的心肌保护途径，其保护机制最终作用于线粒体，但其线粒体机制有待深入研究。目的总结IPO心肌保护作用中线粒体机制的研究进展。内容IPO心肌保护机制通过诱导内源性触发因子（如内源性腺苷的释放），激活再灌注损伤补救激酶（reperfusion injury salvage kinase, RISK）和生存活化因子增强（survival activation factor enhancement, SAFE）等内源性信号转导途径，然后激活信号转导及转录激活因子3（signal transduction and activator of transcription 3, STAT3）、蛋白激酶C（protein kinase C, PKC），促进糖原合酶激酶-3β（glycogen synthase kinase-3β, GSK-3β）磷酸化，开放线粒体敏感性钾离子通道（mitochondrial ATP-sensitive potassium channel, mitoKATP通道）和关闭线粒体通透性转换孔（mitochondrial permeability transition pore, mPTP），通过增加线粒体心磷脂、缝隙连接蛋白43（connexin 43, Cx43）及抗凋亡基因Bcl-2的表达，使线粒体型硫氧还蛋白（thioredoxin, Trx）2及线粒体呼吸链的结构及功能完整，从而减轻MI/RI。趋向IPO心肌保护作用，包括合并糖尿病患者，其机制与线粒体密切相关，但其具体机制尚需进一步研究，以期找到减轻MI/RI、尤其合并糖尿病MI/RI的新靶点，以造福广大心血管患者。

BackgroundMyocardial ischemia/reperfusion injury （MI/RI） is life-threaten to the patients with cardiovascular diseases, and is a serious risk factor for the mortality of patients with diabetes mellitus. Ischemic postconditioning （IPO） effectively protects myocardia probably by strengthening the function of mitochondria.ObjectiveTo summarize mitochondrial mechanisms underlying myocardial protection after IPO.ContentIPO protects myocardia probably by activating endogenous signal transduction pathways, involved in reperfusion injury salvage kinase（RISK） and survival activation factor enhancement（SAFE）, followed by the release of endogenous trigger factors, such as adenosine. Adenosine can activate signal transduction and activator of transcription 3 （STAT3） and protein kinase C （PKC）, then promote the phosphorylation of glycogen synthase kinase-3β （GSK-3β） , open mitochondrial sensitive potassium （mitoKATP） channel, and shut off mitochondrial permeability transition pores （mPTP） by increasing the expression of mitochondrial cardiolipin, connexin 43 （Cx43） and anti-apoptosis gene Bcl-2, thereafter remaining thioredoxin （Trx）2 and mitochondrial respiratory chain intact, and reduce MI/RI.TrendIPO protects myocardia in patients with diabetes mellitus by maintaining homeostasis of mitochondria. However, further investigations are needed to validate the proposed underlying mechanisms of myocardial protection by IPO, especially in diabetic MI/RI, and to confirm some specific signal transduction pathways as new therapeutic targets for MI/RI.