Involvement of cytokines in the mechanism of whole-body hyperthermia-induced cardioprotection

Background-Hyperthermia increases cardiac tolerance to ischemia/reperfusion injury and activates manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger, in myocardium in a biphasic manner. Tumor necrosis fact or-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) induced a biphasic cardioprotection that corresponded to the activation of Mn-SOD. However, a direct association between Mn-SOD activation in myocardium and the acquisit ion of tolerance to ischemia/reperfusion injury induced by hyperthermia and the involvement of the cytokines in the signal transduction pathway for th e hyperthermia-induced cardioprotection have not yet been elucidated. Methods and Results-Hyperthermia was induced in anesthetized rats by placem ent in a temperature-controlled water bath. At 0.5 and 72 hours after hyper thermia, ischemia was induced by occlusion of the left coronary artery for 20 minutes, followed by reperfusion for 48 hours. Inhibition of the increas es in Mn-SOD content and activity 72 hours after hyperthermia by the admini stration of antisense oligodeoxynucleotides to Mn-SOD abolished the expecte d decrease in myocardial infarct size. The simultaneous administration of n eutralizing antibodies to TNF-alpha and IL-1 beta before hyperthermia aboli shed the biphasic cardioprotection and increase in Mn-SOD activity. Conclusions-The increase in Mn-SOD activity mediated through the production of TNF-alpha and IL-1 beta by whole-body hyperthermia is important in the acquisition of early- and late-phase cardioprotection against ischemia/repe rfusion injury in rats.