Copyright © 2006, European Society of Cardiology
Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation
aCardiac Physiology (Cardiovascular Division), The Rayne Institute, St Thomas' Hospital, King's College London, SE1 7EH, UK
bNMR Laboratory (Division of Imaging Sciences), King's College London, SE1 9RT, UK
cThe Hatter Cardiovascular Institute, University College London, WC1E 6HX, UK
dMitochondrial Biology Group (Department of Physiology), University College London, WC1E 6BT, UK
* Corresponding author. Tel.:+44 20 7188 0945; fax:+44 20 7188 3902. Email address: michael.shattock{at}kcl.ac.uk
Objective: Both KATP channel opening drugs and ischaemic preconditioning have been suggested to protect the ischaemic heart by acting on KATP 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 KATP channel and partially uncouple the mitochondria and establish whether this activates protective pathways within the rat heart analogous to KATP 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 µM), 5-hydroxydecanoate (5-HD: 100 µM), N-acetyl cysteine (4 mM), or N-2-mercaptopropionyl glycine (1 mM). The metabolic consequences of FCCP perfusion in isolated hearts were studied using 31P 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 KATP channel activation.
KEYWORDS Mitochondria; Preconditioning; Cardioprotection; Isolated heart; Rat; Ischaemia; Reperfusion; Metabolic inhibition; FCCP; Signalling
1 Present address: Facultad Ciencias de la Salud, Universidad Andres Bello, Republica 217, Santiago, Chile.
Time for primary review 29 days
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