Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS.
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.
Akita
Yuzo
Y
2nd Department of Internal Medicine, Division of Cardiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, 570-8507, Japan.
Otani
Hajime
H
Matsuhisa
Seiji
S
Kyoi
Shiori
S
Enoki
Chiharu
C
Hattori
Reiji
R
Imamura
Hiroji
H
Kamihata
Hiroshi
H
Kimura
Yutaka
Y
Iwasaka
Toshiji
T
D000818:Animals; D004789:Enzyme Activation; D005081:Exercise Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal / Q000379:methods*; D005082:Physical Exertion; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000502:physiology
D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse