Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1723-41. doi: 10.1152/ajpheart.00553.2011. Epub 2011 Aug 19.
Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.
由于心肌缺血导致的心脏病，如心肌梗死或缺血性心力衰竭，是发达国家的主要死亡原因，而其数量不幸仍在上升。对缺血再灌注损伤病理生理学的初步探索，以及临床证据的积累，导致了缺血预处理的发现，这是三十多年来关于如何减轻缺血再灌注损伤的主要假说。缺血再灌注损伤和预处理诱导的心脏保护的亚细胞病理生理学机制尚未得到很好的理解，但对包括自分泌物质、离子通道、受体、亚细胞信号级联和线粒体调节剂在内的成分以及调节这些成分的策略的广泛研究已经取得了进展。由于基础和临床证据的积累，发现并确立了具有心脏保护潜力的缺血后处理的想法，使得在缺血再灌注损伤后可以将这些知识应用于临床环境。另一个巨大的成果是开展了转化研究，将缺血再灌注损伤的基础发现应用于针对缺血性心脏病的实际临床治疗。在这篇综述中，我们讨论了缺血再灌注损伤的基本病理生理学机制、缺血预处理和后处理的相关保护机制、针对缺血再灌注损伤的分子、药理学或机械治疗的潜在靶点，以及通过调节亚细胞信号机制（特别是线粒体功能）随后产生的不良后果。我们还回顾了正在进行的转化临床试验，以及需要克服的现存临床合并症，以使这些试验适用于临床医学。
