Intracellular signal transduction via acitive oxygen production in cardiac myocytes-role of redox regulation in Mn-SOD induction-

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To investigate the role of active oxygen/ oxygen radical metabolism in intracellular signal transduction of myocardial stress response, we examined the production of active oxygen species and the induction of stress proteins in activated cardiac myocytes and the relationship between these two phenomena. In the first year, we demonstrated that hydrogen peroxide was produced in cardiac myocytes stimulated with TNF-α using hydrogen peroxide sensitive dye, DCFH. TNF-α also augmented Mn-SOD expression in cardiac myocytes. Because 2-mercaptopropionyl glycine (MPG), which scavenge hydrogen peroxide, blocked Mn-SOD induction in cardiac myocytes by TNF-α hydrogen peroxide produced by TNF-α in cardiac myocytes directly linked to the expression of Mn-SOD. In the second year, we examined whether the induction of Mn-SOD in cardiac myocytes by TNF-α occurred in vivo. In treadmill exercise model of rat, concentration of TNFα and IL-1β in cardiac myocytes increased soon after exercise together with the augmentation of Mn-SOD protein and activity 48 hr after exercise. Antibody to TNFα and IL-1β attenuated the induction of Mn-SOD by exercise. MPG could also attenuated Mn-SOD induction by exercise. These results suggest that physical stress such as exercise produced cytokines in cardiac myocytes and the cytokines, thus produced, induced antioxidative enzyme, Mn-SOD, in myocardium through the activation of signal transduction pathway mediated by hydrogen peroxide.