Role of CaMKII in hydrogen peroxide activation of ERK1/2, p38 MAPK, HSP27 and actin reorganization in endothelial cells

  • Nguyen A
  • Chen P
  • Cai H
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Abstract

Growing evidence suggests that reactive oxygen species such as hydrogen peroxide (H2O2) can function as important signaling molecules in vascular cells. H2O2-activated redox-sensitive pathways mediate both physiological and pathological responses given the location and concentration of H2O2. We showed previously for the first time that calcium/calmodulin-dependent protein kinase II (CaMKII) is redox-sensitive in endothelial cells, mediating H2O2upregulation of endothelial nitric oxide synthase. This response is always accompanied by an elongation phenotype of endothelial cells, implying modulation of actin cytoskeleton. In the present study, we investigated the role of CaMKII in H2O2activation of p38 MAPK/heat shock protein 27 (HSP27) pathway and ERK1/2, both of which have been known to regulate actin reorganization in endothelial cells. Addition of H2O2to bovine aortic endothelial cells increased ERK1/2 phosphorylation and activity, which was attenuated by a specific inhibitor of CaMKII, KN93. KN93 also prevented H2O2activation of p38 MAPK. Transfection of endothelial cells with a CaMKII-specific inhibitory peptide (AA 281-309) reduced H2O2phosphorylation of p38 MAPK and ERK1/2. Furthermore, blockade of CaMKII or janus kinase 2 (JAK2, downstream of CaMKII) prevented H2O2activation of HSP27. KN93 attenuated, whereas AG490 (JAK2 inhibitor) abolished, H2O2-induced formation of actin stress fibers. Blockade of ERK1/2 inhibited H2O2phosphorylation of HSP27 transiently. It also partially prevented H2O2induction of actin stress fibers. In summary, redox-sensitive activation of p38 MAPK/HSP27 pathway or ERK1/2 in endothelial cells requires CaMKII. These pathways are at least partially responsible for H2O2induced reorganization of actin cytoskeleton. © 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

Author-supplied keywords

  • Actin cytoskeleton
  • Calcium/calmodulin-dependent protein kinase II
  • ERK1/2
  • Heat shock protein 27
  • Hydrogen peroxide
  • Janus kinase 2
  • p38 MAPK

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Authors

  • Andrew Nguyen

  • Peng Chen

  • Hua Cai

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