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    Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.

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    75
    Author
    Hausenloy, DJ; Lim, SY; Ong, S-G; Davidson, SM; Yellon, DM
    Date
    2010-10-01
    Source Title
    Cardiovascular Research
    Publisher
    Oxford University Press (OUP)
    University of Melbourne Author/s
    Lim, Shiang
    Affiliation
    Surgery (St Vincent's)
    Metadata
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    Document Type
    Journal Article
    Citations
    Hausenloy, D. J., Lim, S. Y., Ong, S. -G., Davidson, S. M. & Yellon, D. M. (2010). Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.. Cardiovasc Res, 88 (1), pp.67-74. https://doi.org/10.1093/cvr/cvq113.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259202
    DOI
    10.1093/cvr/cvq113
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936122
    Abstract
    AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

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