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1 Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA
2 Cardiothoracic Surgery, Emory School of Medicine, Atlanta, GA, USA
3 Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Anesthesiology, University of Massachusetts Medical School, Worcester, MA, USA
* To whom correspondence should be addressed. E-mail: Karin.Przyklenk{at}umassmed.edu.
Emerging evidence suggests that restoration of blood flow in a stuttering manner may limit lethal myocardial ischemia/reperfusion injury. However, the mechanisms contributing to this phenomenon, termed 'postconditioning' (Post-C), remain poorly defined. Our aim was to test the hypothesis that activation of classic 'survival kinases', phosphatidylinositol-3-kinase (PI3-kinase) and/or extracellular-signal regulated kinase (ERK) 1/2, may play a role in postconditioning-induced cardioprotection. In Protocol 1, isolated buffer-perfused rabbit hearts underwent 30 minutes of sustained coronary artery occlusion, and were randomized to receive abrupt reperfusion (controls) or 4 cycles of 30-sec reperfusion/30-sec reocclusion prior to full restoration of flow (Post-C). Protocol 2 was identical, except control and Post-C hearts received the PI3-kinase inhibitor LY 294002 (Protocol 2A) or the ERK 1/2 antagonist PD 98059 (Protocol 2B) throughout the first 25 minutes of reperfusion, while, in Protocol 3, myocardial samples were obtained during the early minutes of reflow from additional control, Post-C and non-ischemic sham hearts for the assessment, by standard immunoblotting, of phospho-Akt (downstream target of PI3-kinase) and phospho-ERK. Protocols 1 and 2: (i) corroborated that infarct size (delineated by tetrazolium staining and expressed as a % of the risk region) was reduced in Post-C hearts versus controls; and (ii) revealed that Post-C-induced cardioprotection was maintained despite LY treatment, but was abrogated by PD 98059. These pharmacologic data were supported by Protocol 3, showing increased immunoreactivity of phospho-ERK, but not phospho-Akt, with Post-C. Thus, our results implicate the involvement of ERK 1/2, rather than PI3-kinase/Akt, in the reduction of infarct size achieved with postconditioning.
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