Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2

Abstract

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 post-C-induced cardioprotection. In protocol 1, isolated buffer-perfused rabbit hearts underwent 30 min of sustained coronary artery occlusion and were randomized to receive abrupt reperfusion (controls) or four cycles of 30 s of reperfusion and 30 s of reocclusion before full restoration of flow (post-C). Protocol 2 was identical except control and postconditioned hearts received the PI3-kinase inhibitor LY-294002 (protocol 2A) or the ERK1/2 antagonist PD-98059 (protocol 2B) throughout the first 25 min of reperfusion, whereas in protocol 3, myocardial samples were obtained during the early minutes of reflow from additional control, postconditioned, and nonischemic sham hearts for the assessment, by standard immunoblotting, of phospho-Akt (downstream target of PI3-kinase) and phospho-ERK. Protocols 1 and 2 corroborated that infarct size (delineated by tetrazolium staining and expressed as a percent of risk region) was reduced in postconditioned hearts vs. control hearts and also revealed that post-C-induced cardioprotection was maintained despite LY-294002 treatment but was abrogated by PD-98059. These pharmacological data were supported by protocol 3, which showed increased immunoreactivity of phospho-ERK but not phospho-Akt with post-C. Thus our results implicate the involvement of ERK1/2 rather than PI3-kinase/Akt in the reduction of infarct size achieved with post-C.

Avaliação do pós-condicionamento isquêmico no tratamento da isquemia mesentérica: estudo experimental em ratos

“…These results were also obtained by Darling et al [21] in an experimental study that assessed infarction in rabbit hearts. The IPostC was able to minimize the area of infarction in comparison to the control group, by performing four cycles of ischemia and reperfusion lasting 30 seconds before initiation of the reperfusion phase.…”

Role of Erk1/2, p70s6K, and eNOS in isofluraneinduced cardioprotection during early reperfusionin vivo

“…18 Erk1/2 was very recently also implicated in ischemic postconditioning. 14 Toma et al recently showed that Erk1/2 mediates desflurane-induced preconditioning. 16 The adenosine A 1 /A 2 subtype receptor agonist 5'-(N-ethylcardoxamido) adenosine (NECA) and bradykinin administered during early reperfusion reduced infarct size by activation of Erk1/2 in isolated rabbit hearts.…”

“…13 Activation of Erk1/2 has been proposed as a redundant mechanism by which downstream elements of the PI3K-Akt cascade may be stimulated to favourably modulate reperfusion injury. 13 The extracellular signal-related kinases mediate ischemic 14 and pharmacological postconditioning, 10,15 and also play important roles in preconditioning produced by the volatile anesthetic desflurane. 16 Thus, the current investigation tested the hypothesis isoflurane-induced postconditioning is dependent on activation of Erk1/2.…”

Role of mitochondrial function in the protective effects of ischaemic postconditioning on ischaemia/reperfusion cerebral damage

“…16 Experimental and clinical studies have indicated the protective effects of postconditioning in ischaemia/reperfusion injury. [17][18][19][20][21] This protection is not only associated with inhibition of inflammation and apoptosis, 22,23 but also with attenuation of oxidative stress. 3,24 The aim of the present study was to use a rat model of ischaemia/ reperfusion injury to evaluate the effects of ischaemic postconditioning on mitochondrial ROS production, in order to determine whether its inhibitory effects on oxidative stress are mediated via the mitochondrial pathway, since the golgi apparatus is also a source of ROS.…”