Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.
Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.
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DOI：
10.1093/cvr/cvq113
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发表时间：
2010-10-01
影响因子：
10.8
通讯作者：
Yellon DM
中科院分区：
文献类型：
--
作者：
Hausenloy DJ;Lim SY;Ong SG;Davidson SM;Yellon DM
线粒体活性氧（ROS）、Akt和Erk 1/2以及最近的线粒体通透性转换孔（mPTP）可能是缺血预处理（IPC）的介质，但这些介质之间的相互作用尚不清楚。本研究的目的是确定IPC是否需要mPTP的亲环素-D（CYPD）组分来产生线粒体ROS并随后激活Akt和Erk 1/2。始终使用缺乏CYPD的小鼠（CYPD-/-）和B6 Sv 129野生型（WT）小鼠。我们已经证明，在基础条件下，发生非病理性mPTP开放（由线粒体钙黄绿素荧光的减少百分比表示）。WT心肌细胞中的这种效应大于CYPD−/−心肌细胞（53 ± 2%WT vs. 17 ± 3%CYPD −/−; P < 0.01），低氧预处理（HPC）增强了这种效应（70 ± 9%WT vs. 56 ± 1%CYPD −/−; P < 0.01）。HPC减少WT模拟缺血再灌注损伤后的细胞死亡（23.2 ± 3.5%HPC vs. 43.7 ± 3.2%WT; P < 0.05），但不能减少CYPD−/−心肌细胞（19.6 ± 1.4%HPC vs. 24.4 ± 2.6%对照; P > 0.05）。HPC在WT中产生线粒体ROS（增加4倍; P < 0.05），但不产生CYPD−/−心肌细胞。HPC在WT心肌细胞中诱导显著的Akt磷酸化（增加两倍; P < 0.05），该作用被环孢素A（CYPD抑制剂）和N-2-巯基丙酰甘氨酸（ROS清除剂）消除。最后，成年小鼠心脏的体内IPC导致WT心脏中Akt和Erk 1/2的显著磷酸化，而不是CYPD−/−心脏。IPC需要mPTP的CYPD组分来产生线粒体ROS并磷酸化Akt和Erk 1/2，这是IPC信号通路中的主要步骤。
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.
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影响因子：
64.5
作者：
Ichas, F;Jouaville, LS;Mazat, JP
通讯作者：
Mazat, JP
影响因子：
5.3
作者：
Lim SY;Davidson SM;Paramanathan AJ;Smith CC;Yellon DM;Hausenloy DJ
通讯作者：
Hausenloy DJ
影响因子：
10.8
作者：
Lim, Shiang Y.;Davidson, Sean M.;Hausenloy, Derek J.;Yellon, Derek M.
通讯作者：
Yellon, Derek M.
影响因子：
4
作者：
De Giorgi, F;Lartigue, L;Ichas, F
通讯作者：
Ichas, F
影响因子：
20.1
作者：
Forbes, RA;Steenbergen, C;Murphy, E
通讯作者：
Murphy, E