HYPOXIA AND HYPOXIA REOXYGENATION ACTIVATE P65(PAK), P38MITOGEN-ACTIVATED PROTEIN-KINASE (MAPK), AND STRESS-ACTIVATED PROTEIN-KINASE (SAPK)IN CULTURED RAT CARDIAC MYOCYTES/

We previously reported that both hypoxia and hypoxia followed by reoxy genation (hypoxia/reoxygenation) rapidly activate Src family tyrosine kinases and p21(ras) in cultured rat cardiac myocytes. This was follow ed by the sequential activation of mitogen-activated protein kinase ki nase kinase (MAPKKK) activity of Raf-1, MAP kinase kinase (MAPKK), MAP Ks (p44(mapk) and p42(mapk), also called extracellular signal-regulate d protein kinase [ERK]1 and ERK2, respectively), and S6 kinase (p90(rs k)). In this study, we demonstrated that both hypoxia and hypoxia/reox ygenation caused rapid activation of stress-activated MAPK signaling c ascades involving p65(PAK), p38MAPK, and SAPK. These stimuli also caus ed phosphorylation of activating transcription factor (AFT)-2, Because p65(PAK) is known to be upstream of p38MAPK and also be a target of p 21(rac-1), which belongs to the rho subfamily of p21(ras)-related smal l GTP-binding proteins, these results strongly suggested that two diff erent stress-activated MAPK pathways distinct from the classical MAPK pathway were activated in response to hypoxia and hypoxia/reoxygenatio n in cardiac myocytes. (C) 1997 Academic Press.