J. Exp. Med., Volume 189, Number 11, June 7, 1999 1699-1706

Exercise Provides Direct Biphasic Cardioprotection via Manganese Superoxide Dismutase Activation

By Nobushige Yamashita,^* Shiro Hoshida,^* Kinya Otsu,^* Michio Asahi,^* Tsunehiko Kuzuya,^* and Masatsugu Hori^*

From the ^* Division of Cardiology,  The First Department of Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan; and the  Cardiovascular Division, Osaka Rosai Hospital, Sakai, Osaka 591-8025, Japan

Epidemiologic investigations have shown that exercise reduces morbidity and mortality from coronary artery disease. In this study, using a rat model, we attempted to determine whether exercise can reduce ischemic injury to the heart and elucidate a mechanism for the cardioprotective effect of exercise. Results showed that exercise significantly reduced the magnitude of a myocardial infarction in biphasic manner. The time course for cardioprotection resembled that of the change in manganese superoxide dismutase (Mn-SOD) activity. The administration of the antisense oligodeoxyribonucleotide to Mn-SOD abolished the expected decrease in infarct size. We showed that the level of tumor necrosis factor  (TNF-) and interleukin 1 (IL-1) increased after exercise. The simultaneous administration of the neutralizing antibodies to the cytokines abolished the exercise-induced cardioprotection and the activation of Mn-SOD. Furthermore, TNF- can mimic the biphasic pattern of cardioprotection and activation of Mn-SOD. An antioxidant completely abolished cardioprotection and the activation of Mn-SOD by exercise or the injection of TNF- as well as exercise-induced increase in TNF- and IL-1. The production of reactive oxygen species and endogenous TNF- and IL-1 induced by exercise leads to the activation of Mn-SOD, which plays major roles in the acquisition of biphasic cardioprotection against ischemia/reperfusion injury in rats.

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