© 1997 American Heart Association, Inc.
Articles |
Hypoxia/Reoxygenation Stimulates Jun Kinase Activity Through Redox Signaling in Cardiac Myocytes
the Department of Cell and Molecular Biology, SRI International, 333 Ravenswood Ave, Menlo Park, Calif.
Correspondence to Dr Keith A. Webster, Department of Molecular and Cellular Pharmacology, Rosenstiel Medical Science Building, 6th Floor, University of Miami, 1600 NW Ave, Miami, FL 33136. E-mail kwebster@chroma.med.miami.edu
Hypoxia and reoxygenation are principal components of myocardial ischemia and reperfusion and have distinctive effects on the tissue. Both conditions 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 hypoxia and reoxygenation, we report here that reoxygenation, but not hypoxia alone, caused sustained 
10-fold increases in phosphorylation of the amino-terminal domain of the c-jun transcription factor. The activation was similar to treatments with anisomycin or okadaic acid and correlated with the hypoxia-mediated depression of intracellular glutathione. Reoxygenation-induced c-Jun kinase activity was reduced by preincubating myocytes during the hypoxia phase with the spin-trap agent 
-phenyl N-tert-butylnitrone or with N-acetylcysteine. The kinase activation was also inhibited by the tyrosine kinase inhibitor genistein but not by other protein kinase inhibitors. These results implicate unquenched reactive oxygen intermediates as the stimulus that initiates a kinase pathway involving the stress-activated protein kinases (JNKs/SAPKs) in reoxygenated cardiac myocytes.
Key Words: ischemia/reperfusion • mitogen-activated protein kinase • stress-activated protein kinase • glutathione • antioxidant
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