Short-term exercise preserves myocardial glutathione and decreases arrhythmias after thiol oxidation and ischemia in isolated rat hearts

Abstract

The purpose of this study was to determine if exercise (Ex) protects hearts from arrhythmias induced by glutathione oxidation or ischemia-reperfusion (I/R). Female Sprague-Dawley rats were divided into two experimental groups: sedentary controls (Sed) or short-term Ex (10 days of treadmill running). Twenty-four hours after the last session, hearts were excised and exposed to either perfusion with the thiol oxidant diamide (200 μM) or global I/R. Ex significantly delayed the time to the onset of ventricular arrhythmia after irreversible diamide perfusion. During a shorter diamide perfusion protocol with washout, Ex significantly decreased the incidence of arrhythmia, as evidenced by a delayed time to the first observed arrhythmia, lower arrhythmia scores, and lower incidence of ventricular fibrillation. Ex hearts exposed to I/R (30-min ischemia/30-min reperfusion) also showed lower arrhythmia scores and incidence of ventricular fibrillation compared with Sed counterparts. Our finding that Ex protected intact hearts from thiol oxidation was corroborated in isolated ventricular myocytes. In myocytes from Ex animals, both the increase in H(2)O(2) fluorescence and incidence of cell death were delayed after diamide. Although there were no baseline differences in reduced-to-oxidized glutathione ratios (GSH/GSSG) between the Sed and Ex groups, GSH/GSSG was better preserved in Ex groups after diamide perfusion and I/R. Myocardial glutathione reductase activity was significantly enhanced after Ex, and this was preserved in the Ex group after diamide perfusion. Our results show that Ex protects the heart from arrhythmias after two different oxidative stressors and support the hypothesis that sustaining the GSH/GSSG pool stabilizes cardiac electrical function during conditions of oxidative stress.

Impact of exercise training on redox signaling in cardiovascular diseases

“…Increased GSH reductase activity after exercise improves the heart's ability to replenish GSH, helping to maintain favorable GSH/GSSG upon oxidant stress. Activation of GSH reductase during exercise occurs through transient ROS production via NADPH oxidase, but not via mitochondria (Frasier et al, 2013). Pharmacological inhibition of either NAPDH oxidase or GSH reductase abolishes exercisemediated cardioprotection.…”

“…Frasier and co-workers have described that short-term exercise preserves cardiac glutathione pools and decreases myocardial damage after thiol oxidation and ischemic insult (Frasier et al, 2011). GSH reductase, the enzyme that reduces GSH disulfide (GSSG) to the sulphydryl form (GSH), seems to be an important downstream target of exercise-mediated ROS signaling (Frasier et al, 2013). Increased GSH reductase activity after exercise improves the heart's ability to replenish GSH, helping to maintain favorable GSH/GSSG upon oxidant stress.…”

Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics

“…Exercise is known to protect against arrhythmia (27,30,36,60), as well as other postischemic damage, such as myocardial stunning (11,46,66) and infarction (14,29,58,59). Despite the clear beneficial effect, the underlying cellular mechanisms are not completely understood.…”

“…Several factors, including various genetic abnormalities, channelopathies, compromised autonomic function, left ventricular hypertrophy, and acute coronary syndromes, are known to influence the susceptibility to arrhythmia (26, 53, 68). During acute coronary syndromes, the reperfusion of previously ischemic tissue leads to a burst in reactive oxygen species (ROS), a significant contributor to electromechanical dysfunction (3,10,48,75).Exercise is known to protect against arrhythmia (27,30,36,60), as well as other postischemic damage, such as myocardial stunning (11,46,66) and infarction (14,29,58,59). Despite the clear beneficial effect, the underlying cellular mechanisms are not completely understood.…”

“…We recently observed that exercise delayed the onset of arrhythmia and decreased the incidence of ventricular fibrillation (VF) through better preservation of redox homeostasis (30). This was attributed to enhanced glutathione reductase (GR) activity, which was essential for cardioprotection (29).…”