Regulation of cardiomyocyte apoptosis by redox-sensitive transcription factors

Reperfusion of ischemic myocardium results in apoptotic cell death and DNA fragmentation. Several transcription factors are known to regulate the apop totic cell death. This study sought to examine the regulation of cardiomyoc yte apoptosis by these transcription factors. Isotated working rat hearts w ere divided into six groups: control, 15 min ischemia, 60 min ischemia, 15 min ischemia followed by 2 h reperfusion, ischemic stress adaptation by sub jecting the hearts to four cyclic episodes to 15 min ischemia, each followe d by 10 min of reperfusion, and adaptation followed by 15 min ischemia and 2 h reperfusion, Redox-regulated transcription factors, NF kappaB and AP-1 and the expression of bro anti- and pro-apoptotic genes, Bel-2 and p53 were determined. The results demonstrated NF kappaB and AP-1 progressively and steadily increased as a function of the duration of ischemia, In the adapte d heart, NF kappaB binding remained high while AP-1 binding was lowered to almost baseline value. The anti-oxidant gene, Bcl-2 was downregulated in th e ischemic/reperfused heart, but upregulated in the preconditioned myocardi um, Significant induction of the expression of p53 occurred after ischemia and reperfusion, Apoptotic cells were barely detected in the adapted myocar dium which was subjected to the same ischemia/reperfusion protocol. The res ults demonstrate for the first time differential regulation of cardiomyocyt e apoptosis by pro- and anti-apoptotic transcription factors and genes as a function of different durations of ischemia and reperfusion. (C) 2000 Fede ration of European Biochemical Societies. Published by Elsevier Science B.V . All rights reserved.