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Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning

Hausenloy, DJ; Lim, SY; Ong, SG; Davidson, SM; Yellon, DM; (2010) Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning. CARDIOVASC RES , 88 (1) 67 - 74. 10.1093/cvr/cvq113.

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Abstract

It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 +/- 2% WT vs. 17 +/- 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 +/- 9% WT vs. 56 +/- 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 +/- 3.5% HPC vs. 43.7 +/- 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 +/- 1.4% HPC vs. 24.4 +/- 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts.The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.

Type: Article
Title: Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning
DOI: 10.1093/cvr/cvq113
Keywords: Cyclophilin-D, Mitochondrial permeability transition pore, Ischaemic preconditioning, Akt, Erk1, 2, Reactive oxygen species, PERMEABILITY TRANSITION PORE, CELL-DEATH, SINGLE MITOCHONDRIA, REPERFUSION INJURY, CARDIAC MYOCYTES, INTACT-CELLS, MYOCARDIUM, MECHANISM, TRANSIENT, PROTECTS
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 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/168443
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