The importance of manganese superoxide dismutase in delayed preconditioning: involvement of reactive oxygen species and cytokines.

It is clinically important to elucidate the mechanism underlying the delayed preconditioning against ischemia-reperfusion injury observed 24-72 h after sublethal stress such as brief ischemia, hyperthermia and exercise. The time course of induction of myocardial manganese-superoxide dismutase (Mn-SOD) and appearance of the ischemic tolerance coincide well, and the percent increase in Mn-SOD activity and percent reduction of infarct size are correlated well under various stresses. Furthermore, treatments with antisense oligodeoxynucleotides to Mn-SOD completely abolished the delayed preconditioning and any increase in Mn-SOD content. These results indicate that Mn-SOD induction plays a pivotal role in the late phase preconditioning afforded with brief ischemia, hyperthermia and exercise. We also showed that cytokines, e.g., tumor necrosis factor-alpha and interleukin-1beta, and reactive oxygen species are involved in the process of signal transduction for the Mn-SOD induction.