Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes

Biochem Biophys Res Commun. 1997 Oct 29;239(3):840-4. doi: 10.1006/bbrc.1997.7570.


We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes. This was followed by the sequential activation of mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1, MAP kinase kinase (MAPKK), MAPKs (p44mapk and p42mapk, also called extracellular signal-regulated protein kinase [ERK]1 and ERK2, respectively), and S6 kinase (p90rsk). In this study, we demonstrated that both hypoxia and hypoxia/reoxygenation caused rapid activation of stress-activated MAPK signaling cascades involving p65PAK, p38MAPK, and SAPK. These stimuli also caused phosphorylation of activating transcription factor (ATF)-2. Because p65PAK is known to be upstream of p38MAPK and also be a target of p21rac-1, which belongs to the rho subfamily of p21ras-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Hypoxia
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Enzyme Activation
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases*
  • Myocardium / cytology
  • Myocardium / enzymology*
  • Oxidation-Reduction
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Transcription Factors / metabolism
  • p21-Activated Kinases
  • p38 Mitogen-Activated Protein Kinases


  • Activating Transcription Factor 2
  • Atf2 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases