Department of Physiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Antioxid Redox Signal. 2011 Mar 1;14(5):821-31. doi: 10.1089/ars.2010.3318. Epub 2010 Aug 30.
Ischemic preconditioning, a robust cardioprotective intervention, has limited clinical efficacy because it must be initiated before myocardial ischemia. Conversely, ischemic postconditioning, repeated brief reocclusions of a coronary artery after release of prolonged coronary occlusion, provides cardioprotection in clinically feasible settings, that is, coronary angioplasty. Ischemic postconditioning's signaling is being investigated to identify pharmacological triggers that could be used without angioplasty. In initial minutes of reperfusion H(+) washes out of previously ischemic cells. pH rises enabling mitochondrial permeability transition pores (MPTPs) to form leading to cessation of ATP production and cell necrosis. Coronary reocclusions maintain sufficient acidosis to keep MPTP closed while signaling is initiated that can generate endogenous antagonists of MPTP formation even after cellular pH normalizes. Reintroduction of oxygen generates reactive oxygen species that activate protein kinase C to increase sensitivity of adenosine A(2b) receptors allowing adenosine released from ischemic cells to bind leading to activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Phosphatidylinositol 3-kinase activation results in phosphorylation of Akt promoting activation of nitric oxide synthase and nitric oxide production, which inhibits glycogen synthase kinase-3β, perhaps the final cytosolic signaling step before inhibition of MPTP formation. Interference with MPTP may be the final step that determines cell salvage.
缺血预处理是一种强大的心脏保护干预措施，但由于必须在心肌缺血之前开始，因此其临床疗效有限。相反，缺血后处理是指在延长的冠状动脉闭塞解除后反复短暂地再闭塞冠状动脉，可在可行的临床环境（即冠状动脉成形术）中提供心脏保护。目前正在研究缺血后处理的信号转导，以确定可以在不进行血管成形术的情况下使用的药理触发因素。在再灌注的最初几分钟内，先前缺血的细胞内 H(+) 被冲洗出来。pH 值升高，使线粒体通透性转换孔 (MPTP) 形成，导致 ATP 产生停止和细胞坏死。冠状动脉再闭塞保持足够的酸中毒，使 MPTP 保持关闭，同时启动信号转导，即使细胞 pH 值恢复正常后，也能产生 MPTP 形成的内源性拮抗剂。重新引入氧气会产生活性氧，激活蛋白激酶 C，增加腺苷 A(2b)受体的敏感性，使缺血细胞释放的腺苷与之结合，从而激活磷酸肌醇 3-激酶和细胞外信号调节激酶 1/2。磷酸肌醇 3-激酶的激活导致 Akt 的磷酸化，促进一氧化氮合酶的激活和一氧化氮的产生，一氧化氮抑制糖原合成酶激酶-3β，这可能是抑制 MPTP 形成之前的最后一个细胞质信号转导步骤。干扰 MPTP 可能是决定细胞挽救的最后一步。
