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Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection

Davidson, SM; Hausenloy, D; Duchen, MR; Yellon, DM; (2006) Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. INT J BIOCHEM CELL B , 38 (3) 414 - 419. 10.1016/j.biocel.2005.09.017.

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Abstract

Post-ischemic interventions that activate phosphatidylinositol-3-OH kinase (PI(3)K)-Akt or ERK1/2 pro-survival kinases (the so-called "reperfusion injury signalling kinase (RISK) pathway") during the first few minutes of reperfusion protect against lethal reperfusion-induced injury. We have previously shown that insulin protects against reperfusion-induced injury via activation of the PI(3)K-Akt pathway. In addition, opening of the mitochondrial permeability transition pore (mPTP) at the time of reperfusion is a major determinant of lethal reperfusion-induced injury, and pharmacologically inhibiting it is cardioprotective. In this study, we examined the relationship between the pro-survival kinase pathways and mPTP opening. Specifically, we tested the hypothesis that activation of the pro-survival kinase pathway by insulin protects cardiomyocytes by reducing the probability of mPTP opening upon reperfusion. Laser illumination of the fluorophore, tetramethyl rhodamine methyl ester (TMRM), was used to induce oxidative stress in the preparation of adult rat ventricular cardiomyocytes. Maintained illumination ultimately induces mPTP opening, detected as a global mitochondrial depolarization, followed by ATP depletion and rigor contracture. Insulin significantly delayed mPTP opening by a factor of similar to 1.7-fold (P < 0.001). The effect of insulin was prevented by Wortmannin and by LY-294002, inhibitors of the PI(3)K pathway, by SH-6, a selective inhibitor of Akt, and by L-NAME, an inhibitor of nitric oxide production. The expression of a dominant negative construct of Akt eliminated the effect of insulin in delaying mPTP opening in a cardiac cell line. Furthermore, the overexpression of constitutively active Akt was sufficient to maximally delay mPTP opening. These results indicate that activation of the PI(3)K-Akt pro-survival kinase pathway inhibits opening of the mPTP, and demonstrate an important link between the survival kinases and the mPTP. (C) 2005 Elsevier Ltd. All rights reserved.

Type: Article
Title: Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection
DOI: 10.1016/j.biocel.2005.09.017
Keywords: signal transduction, growth factors, ischemia, reperfusion, oxygen radicals, ISCHEMIA-REPERFUSION, CELL-DEATH, MYOCARDIAL PROTECTION, OXIDATIVE STRESS, P70S6 KINASE, INSULIN, AKT, MODULATION, ACTIVATION, PHYSIOLOGY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: http://discovery.ucl.ac.uk/id/eprint/104818
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