Rationale: Timely restoration of coronary blood flow is the only way to salvage myocardium from infarction, but reperfusion per se brings on additional injury. Such reperfusion injury and the resulting size of myocardial infarction is attenuated by ischemic postconditioning, ie, the repeated brief interruption of coronary blood flow during early reperfusion. The signal transduction of ischemic postconditioning is under intense investigation, but no signaling step has yet been identified as causal for such protection in larger mammals in situ.
Objective:We have now in an in situ pig model of regional myocardial ischemia/reperfusion addressed the role of mitochondrial signal transducer and activator of transcription 3 (STAT3). Key Words: infarct size Ⅲ mitochondrion Ⅲ myocardial ischemia Ⅲ postconditioning Ⅲ reperfusion M yocardial infarction continues to be a major cause of mortality and morbidity, and infarct size is the major determinant of patients' prognosis. The only way to reduce infarct size is early reperfusion of the occluded coronary artery, but reperfusion not only salvages myocardium but also brings on additional "reperfusion injury." 1-3 Ischemic postconditioning, ie, repeated brief interruption of coronary blood flow during early reperfusion, attenuates such reperfusion injury and reduces ultimate infarct size. 4 Ischemic postconditioning is operative in all species tested so far, including humans. 5,6 The signaling of cardioprotection is still under intense investigation and involves 3 major intracellular pathways, ie, the nitric oxide synthase/protein kinase G program, 7 the reperfusion injury salvage kinase program, 8 and the survival activating factor enhancement 9,10 program, all converging at the mitochondria as an integration point that is decisive for cardiomyocyte survival. 11,12 Signal transducer and activator of transcription 3 (STAT3) is a central element of cardioprotection, 13,14 notably of the survival activating factor enhancement program, and it is activated by phosphorylation at tyrosine 705 and serine 727 during myocardial ischemia and even more during early reperfusion. 15 Ischemic postconditioning increases STAT3 activation beyond that by reperfusion per se, 16 and pharmacological inhibition of STAT3 activation or its genetic ablation abrogates cardioprotection. 17,18 The exact role of STAT3 in cardioprotection is not clear; its established function as a transcription factor that regulates cardioprotective proteins 19 -21 is probably too slow to account for the immediate rescue from cell death during the early minutes of reperfusion. Recently, STAT3 has been identified in cardiomyocyte mitochondria, and its pharmacological inhibition or genetic ablation impaired complex 1 respiration 22-24 and calcium retention capacity. 23 Conversely, a mitochondrial-targeted STAT3 overexpression in mice preserved complex 1 respiration during simulated ex vivo ischemia and reduced the formation of reactive oxygen species. 25 However, an improved mitochondrial function secondary to acute STAT3
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