MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine

Abstract

Objective: The Ca2+-paradox is an important phenomenon to study cell injury induced by Ca2+-overload in myocardium. Although intracellular Ca2+-overload acts as a trigger and modulator of cell death due to apoptosis under various pathophysiological conditions, the presence of apoptosis in hearts subjected to Ca2+-paradox has not been demonstrated. Since taurine attenuates the changes in cardiac function due to Ca2+-paradox, this study investigated the occurrence and mechanisms of apoptosis in Ca2+-paradoxic hearts treated in the absence and presence of taurine. Methods: Ca2+-paradox was induced by perfusing the isolated rat heart with Ca2+-free medium for 5 min followed by reperfusion with Ca2+-containing medium for 30 min. Apoptosis related signal transduction mechanisms were determined in Ca2+-paradoxic hearts perfused with or without 10 mM taurine. Results: Marked alterations in cardiac function and the presence of apoptosis were seen in Ca2+-paradoxic hearts reperfused for 30 min. Unlike the total protein contents in hearts subjected to Ca2+-paradox, the contents of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK)1, ERK2 and c-jun amino-terminal kinase were increased by 125±8.6%, 296±14.3%, 213±8.5% and 133±4.2%, respectively vs. control. Caspase-3 and phosphorylated Bcl-2 contents were also increased by 193±10.2% and 134±5.0% vs. control whereas phosphorylated Bad and the ratio of Bcl-2/Bad were depressed by 32±10.8% and 0.23±0.5% vs. control in Ca2+-paradoxic hearts. The apoptosis as seen in Ca2+-paradoxic hearts reperfused for 30 min was not evident in hearts at 10 min Ca2+-repletion but was similar to hearts subjected to 60 min Ca2+-repletion. These changes in the apoptotic pathway in cardiomyocytes subjected to Ca2+-paradox were prevented by taurine. Furthermore, taurine attenuated the KCl- or ATP-induced increase in intracellular concentration of Ca2+ in cardiomyocytes. Conclusions: This study suggests that cardiac dysfunction due to Ca2+-paradox may be associated with apoptosis. In addition, the beneficial effects of taurine on cardiac function may be related to the attenuation of changes in MAPK and apoptotic signal transduction mechanisms in Ca2+-paradoxic hearts.