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

Abstract

Purpose: Administration of isoflurane during early reperfusion after prolonged coronary artery occlusion decreases myocardial infarct size by activating phosphatidylinositol-3-kinase (PI3K) signal transduction. The extracellular signal-related kinases (Erk1/2) represent a redundant mechanism by which signaling elements downstream from PI3K, including 70-kDA ribosomal protein s6 kinase (p70s6K) and endothelial nitric oxide synthase (eNOS), may be activated to reduce reperfusion injury. We tested the hypothesis Erk1/2, p70s6K, and eNOS mediate isoflurane-induced postconditioning in rabbit myocardium in vivo. Methods: Barbiturate-anesthetized rabbits (n = 78) instrumented for measurement of systemic hemodynamics were subjected to a 30-min coronary occlusion followed by three hours reperfusion. Rabbits were randomly assigned to receive 0.9% saline (control), the Erk1/2 inhibitor PD 098059 (2 mg·kg -1 ), the p70s6K inhibitor rapamycin (0.25 mg·kg -1 ), the nonselective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME; 10 mg·kg -1 ), the selective inducible NOS antagonist aminoguanidine hydrochloride (AG, 300 mg·kg -1 ), or the selective neuronal NOS inhibitor 7-nitroindazole (7-NI, 50 mg·kg -1 ) in the presence or absence of 1.0 minimum alveolar concentration isoflurane administered for three minutes before and two minutes after reperfusion. Results: Brief exposure to 1.0 minimum alveolar concentration isoflurane reduced (P < 0.05) infarct size (21 ± 4% [mean ± SD] of left ventricle area at risk, respectively; triphenyltetrazolium staining) as compared to control (41 ± 5%). PD 098059, rapamycin, and L-NAME, but not AG nor 7-NI, abolished the protection produced by isoflurane. Conclusion:The results suggest that the protective effects of isoflurane against infarction during early reperfusion are mediated by Erk1/2, p70s6K, and eNOS in vivo. Objectif : L'administration d'isoflurane pendant la reperfusion pré-coce qui suit une occlusion prolongée de l'artère coronaire diminue la taille de l'infarctus myocardique en activant la transduction du signal de la phosphatidylinositol-3-kinase (PI3K). Les kinases extracellulaires reliées au signal (Erk1/2) représentent un mécanisme redondant par lequel le signalement des éléments en aval à partir de PI3K, incluant la s6 kinase de protéines ribosomales

Sevoflurane Postconditioning Protects Chronically-Infarcted Rat Hearts against Ischemia-Reperfusion Injury by Activation of Pro-survival Kinases and Inhibition of Mitochondrial Permeability Transition Pore Opening upon Reperfusion

“…Some studies suggested a predominant role for PI3K-PKB/Akt, 11,32) some supported MEK 1/2-ERK 1/2 as the major mediator, 33) the other argued for equally importance for these two cascades. [34][35][36][37] It is difficult to explain the discrepancy of these findings, possible reasons might include the difference in ischemia-reperfusion models, species and the stimuli (e.g. anesthetics) used.…”

“…Similarly, another research group demonstrated in separate studies that both PKB/Akt and ERK 1/2 play an important role in isoflurane-induced cardioprotection. 36,37) Convergence on the common downstream targets, such as p70S6K and BAD may explain, at least partially, the requirement for both PKB/Akt and ERK 1/2 to be activated to mediate protection. 38) The activation of p70S6K requires the phosphorylation at both Thr389 (the site phosphorylated by PKB/Akt) and Thr421, Ser424 (the sites phosphorylated by ERK 1/2), which would necessitate the activation of both the PI3K-PKB/Akt and MEK 1/2-ERK 1/2 cascades to mediate cardioprotection.…”

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

“…Following the introduction of ischemic postconditioning as a cardioprotective strategy [11], and on the background of studies demonstrating the ability of volatile anesthetics to mimic the effects of ischemic preconditioning [128,129] and exert cardioprotection when administered at the time of myocardial reperfusion [130,131], a growing body of studies suggest that volatile anesthetics, when administered at the time of myocardial reperfusion are able to reduce myocardial injury through the recruitment of the RISK pathway [62], and its downstream targets, p70s6K, GSK3b, eNOS, Bcl-2 and the mPTP [63,68] both in the normal [63,64,67] and infarct-remodelled myocardium [65], thereby introducing the concept of 'pharmacological' or 'anesthetic' postconditioning.…”

“…In vivo rabbit hearts [62][63][64][65][66] In vivo rabbit hearts [67] GSK-3b activation [63][64][65]67] P70s6K activation [65,67] Inhibition of mPTP opening [63,64,68] eNOS [65,67] (e) Atorvastatin Perfused mouse hearts [69] Perfused mouse hearts [70] p38 and HSP27 activation using perfused mouse hearts [70] (f) Metformin Perfused rat hearts (Unpublished)…”

Preconditioning and Postconditioning

“…Zhu and coworkers (2006) followed by finding that cardioprotection from postconditioning in the remodeled rat myocardium is regulated through PI3K-AKT signaling. The role of ERK 1/2 was addressed by Darling et al (2005) and Krolikowski et al (2006). Darling and colleagues utilized mechanical postconditioning in isolated rabbit hearts and found ERK1/2 but not PI3K activity provided cardiac protection.…”