Differential roles of p38-MAPK and JNKs in mediating early protection or apoptosis in the hyperthermic perfused amphibian heart

Abstract

SUMMARY In the present study the activation of p38 mitogen-activated protein kinase(p38-MAPK) and c-Jun N-terminal kinases (JNKs) by hyperthermia was investigated in the isolated perfused Rana ridibunda heart. Hyperthermia (42°C) was found to profoundly stimulate p38-MAPK phosphorylation within 0.5 h, with maximal values being attained at 1 h[4.503(±0.577)-fold relative to control, P<0.01]. JNKs were also activated under these conditions in a sustained manner for at least 4 h[2.641(±0.217)-fold relative to control, P<0.01]. Regarding their substrates, heat shock protein 27 (Hsp27) was maximally phosphorylated at 1 h [2.261(±0.327)-fold relative to control, P<0.01] and c-Jun at a later phase [3 h: 5.367(±0.081)-fold relative to control, P<0.001]. Hyperthermia-induced p38-MAPK activation was found to be dependent on the Na+/H+ exchanger 1 (NHE1) and was also suppressed by catalase (Cat) and superoxide dismutase (SOD), implicating the generation of reactive oxygen species (ROS). ROS were also implicated in the activation of JNKs by hyperthermia, with the Na+/K+-ATPase acting as a mediator of this effect at an early stage and the NHE1 getting involved at a later time point. Finally, JNKs were found to be the principal mediators of the apoptosis induced under hyperthermic conditions, as their inhibition abolished poly(ADP-ribose)polymerase (PARP) cleavage after 4 h at 42°C. Overall, to our knowledge,this study highlights for the first time the variable mediators implicated in the transduction of the hyperthermic signal in the isolated perfused heart of an ectotherm and deciphers a potential salutary effect of p38-MAPK as well as the fundamental role of JNKs in the induced apoptosis.