The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/6/1699/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 11, June 7, 1999 1699-1706

Articles

Exercise Provides Direct Biphasic Cardioprotection via Manganese Superoxide Dismutase Activation

Nobushige Yamashita*, Shiro Hoshida*,{ddagger}, 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 {ddagger} 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 {alpha} (TNF-{alpha}) and interleukin 1β (IL-1β) 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-{alpha} 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-{alpha} as well as exercise-induced increase in TNF-{alpha} and IL-1β. The production of reactive oxygen species and endogenous TNF-{alpha} and IL-1β 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.

Key Words: free radical • tumor necrosis factor • interleukin 1 • infarct size • N-2-mercaptopropionyl glycine

Address correspondence to Shiro Hoshida, Cardiovascular Division, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Osaka 591-8025, Japan. Phone: 81-722-52-3561; Fax: 81-722-50-5492; E-mail: hoshidas{at}orh.go.jp

Abbreviations used: ANOVA, analysis of variance; ASODN, antisense oligodeoxyribonucleotide; CAD, coronary artery disease; LCA, left coronary artery; MPG, N-2-mercaptopropionyl glycine; TTC, triphenyltetrazolium chloride; Mn-SOD, manganese superoxide dismutase; SODN, sense oligodeoxyribonucleotide.


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