Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells

Yoshihiro Taniyama, Masuko Fukai, Hirofumi Hitomi, Petra Rocic, Michael J. Kingsley, Chun Pfahnl, David S. Weber, R. Wayne Alexander, Kathy K. Griendling

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Angiotensin II activates a variety of signalling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiostensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser473, but not Thr308. Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attentuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates as VSMC lysates phosporylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosporylation on Ser473. These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.

Original languageEnglish (US)
Pages (from-to)C494-C499
JournalAmerican Journal of Physiology - Cell Physiology
Volume287
Issue number2 56-2
DOIs
StatePublished - Aug 2004
Externally publishedYes

Keywords

  • Mitogen-activated protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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