Abstract
Ischemia postconditioning (IPo) is a promising strategy in reducing myocardial ischemia reperfusion (I/R) injury (MIRI), but its specific molecular mechanism is incompletely understood. Langendorff-perfused isolated rat hearts were subjected to global I/R and received IPo in the absence or presence of the mitochondrial ATP-sensitive potassium channel (mitoKATP) blocker 5-hydroxydecanoate (5-HD). Myocardial mitochondria were extracted and mitochondrial comparative proteomics was analyzed. IPo significantly reduces post-ischemic myocardial infarction and improved cardiac function in I/R rat hearts, while 5-HD basically cancelled IPo’s myocardial protective effect. Joint application of two-dimensional polyacrylamide gel electrophoresis (2DE) and MALDI-TOF MS identified eight differentially expressed proteins between groups. Expression of cardiac succinate dehydrogenase (ubiquinone) flavoprotein subunit (SDHA) increased more than two-fold after I/R, while IPo led to overexpression of dihydrolipoyl dehydrogenase (DLD), NADH dehydrogenase (ubiquinone) flavoprotein 1 and isoform CRA_b (NDUFV1). When the mitoKATP was blocked, MICOS complex subunit Mic60 (IMMT) and Stress-70 protein (Grp75) were over expressed, while DLDH, ATPase subunit A (ATPA) and rCG44606 were decreased. Seven of the differential proteins belong to electron transport chain (ETC) or metabolism regulating proteins, and five of them were induced by closing mitoKATP in I/R hearts. We thus conclude that IPo’s myocardial protective effect relies on energy homeostasis regulation. DLD, SDHA, NDUFV1, Grp75, ATPA and rCG44606 may contribute to IPo’s cardial protective effect.
Highlights
Percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) are effective in mitigating myocardial infarction (MI), myocardial ischemia reperfusion injury (MIRI) induced by reperfusion is always inevitable (Yellon & Hausenloy, 2007)
We found that opening of mitoKATP reduced MIRI (Yang & Yu, 2010; Yu et al, 2011; Yu et al, 2001) and improved energy homeostasis in anoxia/reoxygenation (A/R) cardiomyocytes (Cao et al, 2015)
Ischemia postconditioning (IPo) effectively reduced MIRI induced myocardial hemodynamic dysfunction (Figs. 2A–2D) and myocardium infarction (Fig. 2E), which was partially cancelled by 5-HD treatment
Summary
Percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) are effective in mitigating myocardial infarction (MI), myocardial ischemia reperfusion injury (MIRI) induced by reperfusion is always inevitable (Yellon & Hausenloy, 2007). The beneficial action of IPo is considered to be secondary to its effect on various cellular mechanisms: Janus signal transducer and activator system, reduction of the reactive oxygen or nitrogen species generation, and attenuation of intracellular calcium overload (Heusch, 2013; Heusch, 2015b). All of these mediators decrease lethal reperfusion injury and reduce apoptosis of cardiomyocytes (Heusch, 2013), but IPo’s effects remains controversial in human. The mechanisms by which IPo attenuates cardiac I/R injury need to be further elucidated before its clinical use (Heusch, 2015a)
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