Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation

被引:207
作者
Brennan, Jonathan P.
Southworth, Richard
Medina, Rodolfo A.
Davidson, Sean M.
Duchen, Michael R.
Shattock, Michael J. [1 ]
机构
[1] Kings Coll London, St Thomas Hosp, Rayne Inst, Div Cardiovasc, London SE1 7EH, England
[2] Kings Coll London, NMR Lab, Div Imaging Sci, London SE1 9RT, England
[3] UCL, Hatter Cardiovasc Inst, London WC1E 6HX, England
[4] UCL, Dept Physiol, Mitochondrial Biol Grp, London WC1E 6BT, England
关键词
mitochondria; preconditioning; cardioprotection; isolated heart; rat; ischaemia; reperfusion; metabolic inhibition; FCCP; signalling;
D O I
10.1016/j.cardiores.2006.07.019
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Both K-ATP channel opening drugs and ischaemic preconditioning have been suggested to protect the ischaemic heart by acting on K-ATP channels in the inner mitochondrial membrane, uncoupling the proton gradient and partially dissipating the mitochondrial membrane potential. The aim of these studies was to use low concentrations of FCCP, a mitochondrial protonophore, to bypass the mitochondrial K-ATP channel and partially uncouple the mitochondria and establish whether this activates protective pathways within the rat heart analogous to K-ATP channel openers or preconditioning. Methods: Isolated, Langendorff-perfused rat hearts were subjected to 25 min global zero-flow ischaemia and functional recovery assessed. Hearts were pretreated with FCCP (30-300 nM) in the presence or absence of glibenclamide (1 mu M), 5-hydroxydecanoate (5-HD: 100 mu M), N-acetyl cysteine (4 mM), or N-2-mercaptopropionyl glycine (1 mM). The metabolic consequences of FCCP perfusion in isolated hearts were studied using P-31 NMR, and reactive oxygen species (ROS) production was measured using DCF fluorescence in isolated rat ventricular myocytes. Results: FCCP exerted a dose-dependent cardioprotective effect, with 100 nM FCCP being the optimal concentration. This effect could not be blocked by glibenclamide or 5-HD, but was completely attenuated by N-acetyl cysteine and N-2-mercaptopropionyl glycine. Perfusion with FCCP (100 nM) did not deplete bulk ATP during the pretreatment period but significantly depleted phosphocreatine. In ventricular myocytes, FCCP caused an antioxidant-sensitive increase in ROS production but diazoxide was without effect. Conclusions: In the isolated rat heart, partial mitochondrial uncoupling with low-dose FCCP significantly improves post-ischaemic functional recovery via a ROS-dependent pathway. This cardioprotection is not mediated via the depletion of cellular ATP or mitochondrial K-ATP channel activation. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:313 / 321
页数:9
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