HYPOXIA REOXYGENATION STIMULATES JUN KINASE-ACTIVITY THROUGH REDOX SIGNALING IN CARDIAC MYOCYTES/

Hypoxia and reoxygenation are principal components of myocardial ische mia and reperfusion and have distinctive effects on the tissue. Both c onditions have been associated with inflammation, necrosis, apoptosis, and myocardial infarction. Using a cell culture model of ischemia and reperfusion in which cardiac myocytes were exposed to cycles of hypox ia and reoxygenation, we report here that reoxygenation, but not hypox ia alone, caused sustained approximate to 10-fold increases in phospho rylation of the amino-terminal domain of the c-jun transcription facto r. The activation was similar to treatments with anisomycin or okadaic acid and correlated with the hypoxia-mediated de pression of intracel lular glutathione. Reoxygenation-induced c-Jun kinase activity was red uced by preincubating myocytes during the hypoxia phase with the spin- trap agent alpha-phenyl N-tert-butylnitrone or with N-acetylcysteine. The kinase activation was also inhibited by the tyrosine kinase Inhibi tor genistein but not by other protein kinase inhibitors. These result s implicate unquenched reactive oxygen intermediates as the stimulus t hat initiates a kinase pathway involving the stress-activated protein kinases (JNKs/SAPKs) in reoxygenated cardiac myocytes.