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Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury

Hausenloy, DJ; Duchen, MR; Yellon, DM; (2003) Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. CARDIOVASC RES , 60 (3) 617 - 625. 10.1016/j.cardiores.2003.09.025.

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Abstract

Objective: The opening of the mitochondrial permeability transition pore (mPTP) in the first few minutes of post-ischaemic reperfusion is a critical determinant of reperfusion-induced cell death. We hypothesised that the novel immunosuppressant, sanglifehrin-A (SFA), given at the time of reperfusion, protects the myocardium from ischaemia-reperfusion injury, by suppressing mPTP opening. Methods: Isolated perfused rat hearts were subjected to 35 min ischaemia/120 min reperfusion, and were treated with (1) SFA (1.0 muM) or (2) DMSO vehicle for the first 15 min of reperfusion or (3) SFA (1.0 muM) after the first 15 min of reperfusion. We examined the effect of SFA on mPTP opening directly, using a myocyte model of oxidative stress. Laser illumination of adult rat myocytes loaded with the fluorophore, TMRM, generates oxidative stress, which induces mPTP opening (represented by mitochondrial membrane depolarisation) followed by rigour contracture. Results: In the isolated perfused heart model, SFA, given during the first 15 min of post-ischaemic reperfusion, reduced the infarct-risk volume ratio from 43.9 +/- 2.5% in the control group to 23.8 +/- 4.2% with SFA (p = 0.001). However, when SFA was given after the first 15 min of reperfusion, there was no change in infarct size (43.8 +/- 5.7% with SFA vs. 43.9 +/- 2.5% in control; p = NS), suggesting that SFA has to be present during the first 15 min of reperfusion to induce protection. In the isolated adult myocyte model, SFA was shown to inhibit mPTP opening in the setting of oxidative stress, represented by an increase in the ROS threshold required to induce: mitochondrial membrane depolarisation (from 269 +/- 21 to 777 +/- 100 s; p < 0.00 1) and rigour contracture (from 613 +/- 14 to 1329 +/- 129 s; p < 0.001). Conclusions: Inhibiting mPTP opening during the first few minutes of reperfusion, using sanglifehrin-A, limits infarct size and protects myocytes from oxidative stress. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Type: Article
Title: Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury
DOI: 10.1016/j.cardiores.2003.09.025
Keywords: infarction, ischaemia, membrane permeability, membrane potential, reperfusion, CA-2&-INDUCED MEMBRANE TRANSITION, ADENINE-NUCLEOTIDE TRANSLOCASE, CYCLOSPORINE-A, OXIDATIVE STRESS, HEART-MITOCHONDRIA, CA-2+-DEPENDENT PORE, INORGANIC-PHOSPHATE, RAT CARDIOMYOCYTES, SIMULATED ISCHEMIA, CYCLOPHILIN-D
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/154397
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