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 hours. Induction of these transcripts occurred before any significant loss of intracellular
ATP. In the present study, the origin of the signal(s) that regulates immediate-early gene induction was investigated by comparing the effects of
hypoxia with those of the metabolic inhibitors
cyanide,
deoxyglucose and
cyanide combined, and
iodoacetic acid.
Cyanide, an inhibitor of oxidative metabolism, closely mimicked the metabolic effects of
hypoxia, with elimination of oxygen consumption, increased
lactate production, and minimal decline in
ATP levels under both conditions. Compared with
hypoxia,
cyanide mediated small transient inductions of fos and jun transcripts that followed a different time course. The combination of
cyanide and
deoxyglucose resulted in inhibition of
lactate production as well as respiration, and
ATP dropped rapidly to 20% of control levels. The loss of intracellular
ATP was followed 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 major (90%) loss of
ATP and irreversible cell damage as measured by leakage of
creatine phosphokinase enzyme and loss of membrane
arachidonic acid;
ATP loss was followed by fivefold to sevenfold inductions of c-fos, c-jun and jun B transcripts.(ABSTRACT TRUNCATED AT 250 WORDS)