Abstract P221: Inhibition of Mitochondrial Permeability Transition Pore by Estrogen via P38 and Erk Phosphorylation Preserves the Respiratory Chain and Provides Cardioprotection Against Ischemia-Reperfusion Injury
Introduction: In this study, we investigated the effects of 17β-estradiol (E2) on the opening of mitochondrial permeability transition pore, mitochondrial reactive oxygen species as well on the myocardial infarct size and function recovery after global myocardial ischemia-reperfusion injury.
Methods: Hearts of male mice were isolated and retrograde-perfused through aorta with the Langendorff system at 37°C. After 20 min of perfusion, hearts were subjected to 20min global normothermic ischemia followed by 40min reperfusion. Hearts were perfused with Krebs Henseleit (KH) solution or KH+E2(40nM) or KH+E2(40nM)+ICI 182,780(100nM) and oxygenated with 95% O2 and 5% CO2. After the reperfusion, infarct size was evaluated by triphenyltetrazolium chloride staining and the heart function recovery was measure using a Power Lab (ADInstruments). Mitochondria were isolated to measure calcium retention capacity (CRC) and reactive oxygen species (ROS) production by the complexes I and III of respiratory chain using the specific substrates as well protein level of pP38, pErk and vinculin was expressed by western blot analysis in whole cell lysate after 10min of reperfusion.
Results: The E2-treated group had increased mitochondrial CRC (0.73+0.11μM vs. 1.3+0.06, p<0.01), a reduced infarct size (43±3% vs. 68±5%, p<0.001), an increased pP38 and pErk phosphorylation expression and all heart functional parameters were improved compared to control group. The ROS production by the complex I was similar in all groups but the ROS production by the complex II was increased significantly with E2 treatment (similar to sham) compared to control. The estrogen receptor antagonist ICI 182,780 abolished all these E2-induced effects.
Conclusion: These results indicate that acute E2 exposure favors CRC by inhibiting the mPTP opening resulting in a reduction of the infarct size and improvement of heart function recovery and preserves the respiratory chain degradation via P38 and Erk phosphorylation after ischemia and reperfusion.