Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS

Abstract

We investigated the mechanism of exercise-induced late cardioprotection against ischemia-reperfusion (I/R) injury. C57BL/6 mice received treadmill exercise (60 min/day) for 7 days at a work rate of 60-70% maximal oxygen uptake. Exercise transiently increased oxidative stress and activated endothelial isoform of nitric oxide synthase (eNOS) during exercise and increased expression of inducible isoform of NOS (iNOS) in the heart after 7 days of exercise. The mice were subjected to regional ischemia by 30 min of occlusion of the left coronary artery, followed by 2 h of reperfusion. Infarct size was significantly smaller in the exercised mice. Ablation of cardiac sympathetic nerve by topical application of phenol abolished oxidative stress, activation of eNOS, upregulation of iNOS, and cardioprotection mediated by exercise. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine during exercise also inhibited activation of eNOS, upregulation of iNOS, and cardioprotection. In eNOS(-/-) mice, exercise-induced oxidative stress was conserved, but upregulation of iNOS and cardioprotection was lost. Exercise did not confer cardioprotection when the iNOS selective inhibitor 1400W was administered just before coronary artery occlusion or when iNOS(-/-) mice were employed. These results suggest that exercise stimulates cardiac sympathetic nerves that provoke redox-sensitive activation of eNOS, leading to upregulation of iNOS, which acts as a mediator of late cardioprotection against I/R injury.

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

“…Our data indicate that elevated ROS underlies the late preconditioning effect of sulindac and that downstream PKC activation is also necessary for the molecular changes and protective responses. There is an extensive body of work implicating ROS dependent mechanisms in the triggering of delayed preconditioning by ischemia, exercise or other preconditioning stimuli (33)(34)(35)(36)(37). Following the trigger the next step in late preconditioning requires signaling through pathways that involve key protective kinases including PKC epsilon and PKC epsilon/Src containing modules (38,33).…”

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…For example, studies have reported an increase in the expression of superoxide dismutase (7), catalase (44), and heat-shock proteins (HSPs) (44,48) after exercise. Others reported that exercise increases the expression and activity of endothelial NO synthase (eNOS), resulting in an increase in NO levels (1). Still others report that exercise activates ATP-sensitive potassium channels (sarcolemmal and mitochondrial) in cardiovascular tissues (6,57).…”

Clinical cardioprotection and the value of conditioning responses

“…Evidence has been presented that exercise-mediated protection involves PI3K and Akt (243), may require nitric oxide synthase (6), and involves GPCRs that also trigger Precon (45). The question arises then as to how and why exercise retains efficacy with age or disease whereas Precon responses involving common signal elements fail?…”