Ischemic preconditioning, an endogenous protective mechanism in the cardiomyocyte, and its clinical application

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To develop novel strategies for protection of cardiomyocytes from ischemia/reperfusion injury, we have analyzed cytoprotective mechanisms of ischemic preconditioning (PC). PC, a form of adaptation, refers to enhancement of myocardial tolerance against ischemia/reperfusion-induced necrosis by exposing the myocardium to a brief episode of non-lethal ischemia. PC induces the generation of agonists of Gi/Gq protein-coupled receptors and release of TNF-α and HB-EGF. Stimulation of receptors of these agonists provokes activation of multiple signal pathways, including PKC-ε and PI3K/Akt pathways, which ultimately reach to the “end-effector” of cardiomyocyte protection. There are three possible effectors in PC, mitochondrial ATP-sensitive K+ channel (mKATP channel), glycogen synthase kinase-3β (GSK-3β) and connexin-43 (Cx43). Activation of the mKATP channel attenuates mitochondrial dysfunction presumably by suppressing mitochondrial Ca2+ overload during ischemia/reperfusion. The level of phospho-(Ser9)-GSK-3β, a suppressor of mitochondrial permeability transition upon reperfusion, was found to be a determinant of infarct size in vivo. Accelerated closure of the gap junction after the onset of ischemia by PKC- and ERK-mediated Cx43 phosphorylation is suggested to be an adjunctive mechanism of protection, which suppresses propagation of myocyte injury within the area at risk. However, the cytoprotective signaling of PC can be impaired by concurrent diseases such as postinfarct ventricular remodeling. An opener of the mKATP channel is currently being used for myocardial protection, and selective GSK-3β inhibitors are candidates for novel therapy. Further characterization of cytoprotective signaling and effector molecules and elucidation of their modifications by co-morbidity are necessary for the development of clinically applicable agents.
札幌医科大学の論文
2006-12-01

著者

三浦哲嗣
札幌医科大学内科学第二講座

Ischemic preconditioning, an endogenous protective mechanism in the cardiomyocyte, and its clinical application

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