REGULATION OF FOS AND JUN IMMEDIATE-EARLY GENES BY REDOX OR METABOLICSTRESS IN CARDIAC MYOCYTES

We have previously demonstrated coordinate inductions of c-fos, c-jun, jun B, and jun D in cardiac myocytes exposed to hypoxia for 2 to 4 ho urs. Induction of these transcripts occurred before any significant lo ss of intracellular ATP. In the present study, the origin of the signa l(s) that regulates immediate-early gene induction was investigated by comparing the effects of hypoxia with those of the metabolic inhibito rs cyanide, deoxyglucose and cyanide combined, and iodoacetic acid. Cy anide, an inhibitor of oxidative metabolism, closely mimicked the meta bolic effects of hypoxia, with elimination of oxygen consumption, incr eased lactate production, and minimal decline in ATP levels under both conditions. Compared with hypoxia, cyanide mediated small transient i nductions of fos and jun transcripts that followed a different time co urse. The combination of cyanide and deoxyglucose resulted in inhibiti on of lactate production as well as respiration, and ATP dropped rapid ly to 20% of control levels. The loss of intracellular ATP was followe d by fourfold inductions of c-fos and c-jun with minor changes in jun B and jun D transcript levels. Similarly, iodoacetic acid caused a maj or (90%) loss of ATP and irreversible cell damage as measured by leaka ge of creatine phosphokinase enzyme and loss of membrane arachidonic a cid; ATP loss was followed by fivefold to sevenfold inductions of c-fo s, c-jun, and jun B transcripts. We conclude that the hypoxic stress r esponse in neonatal myocytes, which occurs before ATP depletion, canno t be fully accounted for by inhibition of oxidative metabolism or by f actors related to metabolic switching. In contrast, the stress respons e associated with blockage of both aerobic and anaerobic energy metabo lism coincides with and may be related to the loss of cellular ATP and structural cell damage.