Induction of Manganese Superoxide Dismutase in Rat Cardiac Myocytes Increases Tolerance to Hypoxia 24 Hours after Preconditioning

Manganese superoxide dismutase (Mn-SOD) is induced in ischemic hearts 24 h after ischemic preconditioning, when tolerance to ischemia is acquired. We examined the relation-ship between Mn-SOD induction and the protective effect of preconditioning using cultured rat cardiac myocytes. Ex-posure of cardiac myocytes to brief hypoxia (1 h) decreased creatine kinase release induced by sustained hypoxia (3 h) that follows when the sustained hypoxia was applied 24 h after hypoxic preconditioning (57 % of that in cells without preconditioning). The activity and content of Mn-SOD in cardiac myocytes were increased 24 h after hypoxic precon-ditioning (activity, 170%; content, 139 % compared with cells without preconditioning) coincidentally with the acqui-sition of tolerance to hypoxia. Mn-SOD mRNA was also increased 20-40 min after preconditioning. Antisense oligo-deoxyribonucleotides corresponding to the initiation site of Mn-SOD translation inhibited the increases in the Mn-SOD content and activity and abolished the expected decrease in creatine kinase release induced by sustained hypoxia after 24 h of hypoxic preconditioning. Sense oligodeoxyribo-nucleotides did not abolish either Mn-SOD induction or tol-erance to hypoxia. These results suggest that the induction of Mn-SOD in myocytes by preconditioning plays a pivotal role in the acquisition of tolerance to ischemia at a later phase (24 h) of ischemic preconditioning. (J. Clin. Invest. 1994. 94:2193-2199.) Key words: cardiac myocytes- hyp-oxia-reoxygenation * manganese superoxide dismutase * pre-conditioning * antisense oligodeoxyribonucleotide