In heart failure (HF), the increase in cardiac adrenergic tone, while initially beneficial, ultimately contributes to damage to the failing heart. The aim of this study was to evaluate the mechanisms responsible for cell damage during β-adrenergic stimulation in a rabbit volume- and pressure-overload HF model.Methods and Results
Field stimulation (1 Hz) of single left ventricular HF myocytes in combination with β-adrenergic stimulation (isoproterenol, 1 μM) was accompanied by spontaneous pro-arrhythmogenic Ca2+ release (Ca2+ waves), contractile dysfunction, and a robust increase in reactive oxygen species (ROS) production, eventually leading to cell death. Surprisingly, in HF myocytes FAD/FADH2 levels remained reduced and mitochondrial complex II (succinate dehydrogenase) activity was significantly elevated (by 86%). Increased complex II activity, however did not lead to an increase in ADP-dependent respiration, indicative of an electron leak at complex II. Mitochondrial complex I-mediated state-3 respiration was decreased by 77%, while state-2 respiration remained unchanged. Supplementation of HF myocytes with substrate for complex II (10 mM dimethyl-succinate) caused a dramatic increase in rotenone-sensitive mitochondrial ROS generation compared to control cells and to HF cells treated with complex I substrates. Moreover, dimethyl-succinate itself induced spontaneous Ca2+ release in form of Ca2+ waves that was further augmented by isoproterenol. Cell treatment with complex II inhibitor thenoyl-trifluoroacetone (100 μM) significantly decreased mitochondrial ROS generation and normalised isoproterenol-induced Ca2+-transients and cell shortening.Conclusion
Increased activity of mitochondrial complex II in rabbit HF is a major mediator of oxidative stress leading to impairment of Ca2+ handling and contractility.