Attenuation of CHOP-mediated Myocardial Apoptosis in Pressure-overloaded Dominant Negative p38 alpha Mitogen-activated Protein Kinase Mice

Background/Aims: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. Methods: We clarified the role of p38 alpha MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38 alpha MAPK overexpression to seven day pressure overload. Results: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wildtype (WT) and DN p38 alpha mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)- 1 alpha and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 in the WT and DN p38 alpha mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38 alpha mice. Conclusion: Partial inhibition of p38 alpha protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1 alpha/TRAF2 to its downstream molecule, CHOP. Copyright (C) 2011 S. Karger AG, Basel