Treatment with a JNK inhibitor increases, whereas treatment with a p38 inhibitor decreases, H₂O₂-induced calf pulmonary arterial endothelial cell death

Oxidative stress induces apoptosis in endothelial cells (ECs). Reactive oxygen species (ROS) promote cell death by regulating the activity of various mitogen-activated protein kinases (MAPKs) in ECs. The present study investigated the effects of MAPK inhibitors on cell survival and glutathione (GSH) levels upon H₂O₂ treatment in calf pulmonary artery ECs (CPAECs). H₂O₂ treatment inhibited the growth and induced the death of CPAECs, as well as causing GSH deple­tion and the loss of mitochondrial membrane potential (MMP). While treatment with the MEK or JNK inhibitor impaired the growth of H₂O₂-treated CPAECs, treatment with the p38 inhibitor attenuated this inhibition of growth. Additionally, JNK inhibitor treatment increased the proportion of sub-G1 phase cells in H₂O₂-treated CPAECs and further decreased the MMP. However, treatment with a p38 inhibitor reversed the effects of H₂O₂ treatment on cell growth and the MMP. Simi­larly, JNK inhibitor treatment further increased, whereas p38 inhibitor treatment decreased, the proportion of GSH-depleted cells in H₂O₂-treated CPAECs. Each of the MAPK inhibitors affected cell survival, and ROS or GSH levels differently in H₂O₂-untreated, control CPAECs. The data suggest that the exposure of CPAECs to H₂O₂ caused the cell growth inhibi­tion and cell death through GSH depletion. Furthermore, JNK inhibitor treatment further enhanced, whereas p38 inhibitors attenuated, these effects. Thus, the results of the present study suggest a specific protective role for the p38 inhibitor, and not the JNK inhibitor, against H₂O₂-induced cell growth inhibition and cell death.