on April 5, 2004
Published online before print April 5, 2004, doi: 10.1161/01.CIR.0000126294.81407.7D
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Submitted on November 19, 2003
From the Mitochondrial Biology Group, Department of Physiology, University College London, UK (M.D.); and The Hatter Institute and Centre for Cardiology, University College London, UK (D.H., A.W., D.Y.). * To whom correspondence should be addressed. E-mail: hatter-institute{at}ucl.ac.uk.
Background--Transient (low-conductance) opening of the mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate mitochondrial reactive oxygen species (ROS) signaling. We hypothesize that transient mPTP opening and ROS mediate the protection associated with myocardial preconditioning and mitochondrial uncoupling. Methods and Results--Isolated perfused rat hearts were subjected to 35 minutes of ischemia/120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by tetrazolium staining. Inhibiting mPTP opening during the preconditioning phase with cyclosporine-A (CsA, 0.2 µmol/L) or sanglifehrin-A (SfA, 1.0 µmol/L) abolished the protection associated with ischemic preconditioning (IPC) (20.2±3.6% versus 45.9±2.5% with CsA, 49.0±7.1% with SfA; P<0.001); and pharmacological preconditioning with diazoxide (Dzx, 30 µmol/L) (22.1±2.7% versus 46.3±3.0% with CsA, 48.4±5.5% with SfA; P<0.001), CCPA (the adenosine A1-receptor agonist, 200 nmol/L) (24.9±4.5% versus 54.4±6.6% with CsA, 42.6±9.0% with SfA; P<0.001), or 2,4-dinitrophenol (DNP, the mitochondrial uncoupler, 50 µmol/L) (15.7±2.7% versus 40.8±5.5% with CsA, 34.3±3.1% with SfA; P<0.001), suggesting that mPTP opening during the preconditioning phase is required to mediate protection in these settings. Inhibiting ROS during the preconditioning protocols with N-mercaptopropionylglycine (MPG, 1 mmol/L) also abolished the protection associated with IPC (20.2±3.6% versus 47.1±3.8% with MPG; P<0.001), diazoxide (22.1±2.7% versus 56.3±3.8% with MPG; P<0.001), and DNP (15.7±2.7% versus 50.7±6.6% with MPG; P<0.001) but not CCPA (24.9±4.5% versus 26.5±8.4% with MPG; P=NS). Further experiments in adult rat myocytes demonstrated that diazoxide induced CsA-sensitive, low-conductance transient mPTP opening (represented by a 28±3% reduction in mitochondrial calcein fluorescence compared with control; P<0.01). Conclusions--We report that the protection associated with IPC, diazoxide, and mitochondrial uncoupling requires transient mPTP opening and ROS.
Revised on February 18, 2004
Accepted on February 24, 2004
Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection
Derek Hausenloy MBChB,
Key words: ischemia • myocardial infarction • free radicals • reperfusion
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