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 reoxygenation (hypoxia/reoxygenation) rapidly activate Src family tyrosine kinases and p21(ras) in cultured rat cardiac myocytes. This was followed by the sequential activation of mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-l, MAP kinase kinase (MAPKK), MAPKs (p44(mapk) and p42(mapk), also called extracellular signal-regulated protein kinase [ERK]1 and ERK2, respectively), and S6 kinase (p90(rsk)). In this study, we demonstrated that both hypoxia and hypoxia/reoxygenation caused rapid activation of stress-activated MAPK signaling cascades involving p65(PAK), p38MAPK, and SAPK. These stimuli also caused phosphorylation of activating transcription factor (ATF)-2. Because p65(PAK) is known to be upstream of p38MAPK and also be a target of p21(rac-1) which belongs to the rho subfamily of p21(ras)-related small GTP-binding proteins, these results strongly suggested that two different stress-activated MAPK pathways distinct from the classical MAPK pathway were activated in response to hypoxia and hypoxia/reoxygenation in cardiac myocytes.