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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 ...

Ischemic postconditioning, a simple mechanical maneuver at the onset of reperfusion, reduces infarct size after ischemia/reperfusion. After its first description in 2003 by Zhao et al. numerous experimental studies have investigated this protective phenomenon. Whereas the underlying mechanisms and signal transduction are not yet understood in detail, infarct size reduction by ischemic postconditioning was confirmed in all species tested so far, including man. We have now reviewed the literature with focus on experimental models and protocols to better understand the determinants of protection by ischemic postconditioning or lack of it. Only studies with infarct size as unequivocal endpoint were considered. In all species and models, the duration of index ischemia and the protective protocol algorithm impact on the outcome of ischemic postconditioning, and gender, age, and myocardial temperature contribute.

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.

During myocardial ischemia, connexin 43 (Cx43) is dephosphorylated in vitro, and the subsequent opening of gap junctions formed by two opposing Cx43 hexamers was suggested to propagate ischemia/reperfusion injury. Reduction of infarct size (IS) by ischemic preconditioning (IP) involves activation of protein kinase C (PKC) and p38 mitogen activated protein kinase (MAPK), both of which can phosphorylate Cx43. We now studied in anesthetized pigs whether IP impacts on Cx43 phosphorylation by measuring the density of non-phosphorylated and total Cx43 (confocal laser) during normoperfusion and 90-min ischemia in non-preconditioned and preconditioned hearts. Co-localization of PKCalpha, p38MAPKalpha, and p38MAPKbeta with Cx43 and the activity of p38MAPK were assessed. IP by 10 min ischemia and 15 min reperfusion reduced IS. Non-phosphorylated Cx43 remained unchanged during ischemia in preconditioned hearts, while it increased from 35+/-3 to 75+/-8 AU (P<0.05) in non-preconditioned hearts. Co-localization of PKCalpha, p38MAPKalpha, and p38MAPKbeta with Cx43 during ischemia increased only in preconditioned hearts. While the ischemia-induced increase in p38MAPKalpha activity was comparable in preconditioned and non-preconditioned hearts, p38MAPKbeta activity was increased only in preconditioned hearts. Blockade of p38MAPK by SB203580 attenuated the IS-reduction and the increased p38MAPK-Cx43 co-localization by IP. We conclude that IP increases co-localization of protein kinases with Cx43 and preserves phosphorylation of Cx43 during ischemia.