MAPK superfamily plays an important role in daunomycin-induced apoptosis of cardiac myocytes

Background-Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, inc luding cardiac toxicity. In the present study, we investigated the molecula r mechanisms of DM-induced cardiomyocyte impairment. Methods and Results-When cultured cardiac myocytes of neonatal rats were ex posed to 1 mu mol/L DM for 24 hours, many cells became positive for TUNEL s taining, with morphological changes characteristic of apoptosis, Fragmentat ion of DNA into oligonucleosome-size fragments was recognized by agarose ge l electrophoresis in DM-treated myocytes. DM activated 3 members of the mit ogen-activated protein kinase (MAPK) family dose-dependently, such as extra cellular signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinase s, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca2+ chelator s inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activati on of ERKs was also inhibited by overexpression of dominant negative mutant s of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ER K signaling pathway was selectively blocked by a specific MAPK/ERK kinase i nhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MA PK, SB203580, significantly reduced the amount of apoptosis. Conclusions-These results suggest that DM activates MAPKs through reactive oxygen species and Ca2+ and that the MAPK family plays important roles in D M-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from a poptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte ap optosis.