Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection

Abstract

The loss of cardioprotection induced by the NADPH oxidase inhibitor suggests that ROS generated by this enzyme are important mediators of the preconditioning response, which presumably involves NADPH oxidase-induced RyR2 S-glutathionylation.

Regular treadmill exercise restores cardioprotective signaling pathways in obese mice independently from improvement in associated co-morbidities

“…We can hypothesize that a small amount of reactive oxygen species produced during each bout of exercise may trigger the cardiac adaptations. Indeed, studies have demonstrated that cardioprotective effects of exercise or tachycardia were abolished when anti-oxydants are given during exercise [36][37][38].…”

“…This might partly explain potential beneficial adaptations of calcium handling with exercise. Indeed, it has been previously reported that exercise increases ryanodine-S-glutathionylation which inhibits ryanodine-mediated calcium leak [38].…”

NADPH oxidase signaling and cardiac myocyte function

“…In contrast to this study, Sanchez et al [43] reported the presence of Nox2 NADPH oxidase activity in canine cardiac SR and showed that oxidase activation increased S-glutathionylation of ryanodine receptors and hence SR Ca2+ release -effects which were abrogated by apocynin (a purported Nox inhibitor, but which may act as a non-selective antioxidant). The same group also showed that oxidase activity and the effects on SR Ca2+ release were augmented by tachycardia [44]. O2−radical dot produc on by NADPH oxidase on the SR of bovine coronary artery smooth muscle cells has also been shown to regulate calcium-induced calcium release [45].…”

“…However, the myocardium of Nox2−/− mice could s ll be preconditioned by an adenosine receptor agonist. Subsequently, other groups have reported an involvement of NADPH oxidase-derived ROS in the cardiac preconditioning induced by angiotensin II [111] and [112] and tachycardia or exercise [43] and [44].…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…Collectively, the activation of these signaling cascades thus could lead to vasodilation, cell proliferation, injury, or other consequences (17,26,73,142). As ROS and NO are able to modulate thiol groups of many ion channels (1,27,101) including the K ATP channel (21,64,138), which are potentially involved in membrane potential regulation and downstream signaling, we propose that a feedback loop may exist linking membrane potential, ion channel regulation (by S-glutathionylation or S-nitrosylation), The modification of one cysteine by S-glutathionylation has an allosteric effect on another cysteine residue at a different place, modulating its reactivity to S-nitrosylation.…”