Abstract
Hypothermia and hypothermic preconditioning are known to be profoundly cardioprotective, but the molecular mechanisms of this protection have not been fully explained. In this study, temperature preconditioning (16 °C) was found to be cardioprotective in isolated adult rat ventricular myocytes, enhancing contractile recovery and preventing calcium dysregulation after oxidative stress. Hypothermic preconditioning preserved mitochondrial function by delaying the pathological opening of the mitochondrial permeability transition pore (mPTP), whereas transient mPTP flickering remained unaltered. For the first time, reactive oxygen species (ROS) from the mitochondria are shown to be released exclusively during the hypothermic episodes of the temperature-preconditioning protocol. Using a mitochondrially targeted ROS biosensor, ROS release was shown during the brief bursts to 16 °C of temperature preconditioning. The ROS scavenger N-(2-mercaptopropionyl) glycine attenuated ROS accumulation during temperature preconditioning, abolishing the protective delay in mPTP opening. Temperature preconditioning induces ROS-dependant phosphorylation of the prosurvival kinase extracellular signal-regulated kinase (ERK)1/2. ERK1/2 activation was shown to be downstream of ROS release, as the presence of a ROS scavenger during temperature preconditioning completely blocked ERK1/2 activation. The cardioprotective effects of temperature preconditioning on mPTP opening were completely lost by inhibiting ERK1/2 activation. Thus, mitochondrial ROS release and ERK1/2 activation are both necessary to signal the cardioprotective effects of temperature preconditioning in cardiac myocytes.
Highlights
The situation is exacerbated as mitochondria begin to consume ATP through reversal of the F1/F0 ATPase in an effort to maintain the mitochondrial membrane potential.[3]
To investigate the molecular mechanisms of temperature preconditioning in cardioprotection, adult rat hearts were dissociated into single ventricular myocytes and subjected to simulated ischaemia/reperfusion injury
The results of this study demonstrate that temperature preconditioning by two brief episodes of profound hypothermia (16 1C) results in strong cardioprotection of isolated ventricular myocytes against oxidative stress
Summary
The situation is exacerbated as mitochondria begin to consume ATP through reversal of the F1/F0 ATPase in an effort to maintain the mitochondrial membrane potential.[3]. Strong evidence suggests that inhibiting the mPTP is a powerful means to protect the heart against ischaemia/ reperfusion injury.[4,5] One example of an mPTP inhibitor is cyclosporine A (CsA), which binds to cyclophilin-D, a core component of the mPTP. In addition to irreversible mPTP opening, the mPTP has been reported to flicker,[9] which may serve as a way for mitochondria to remove excess mitochondrial reactive oxygen species (ROS) and calcium during respiration.[10]. Cardioprotection is a phenomenon whereby the myocardium can be protected from damage by ischaemia/reperfusion injury. Hypothermia is considered to be one of the most potent cardioprotective strategies available and is used clinically to protect the heart against ischaemia in a number of surgical
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