Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells

Masuko Ushio-Fukai, R. Wayne Alexander, Marjorie Akers, Qi Qin Yin, Yasushi Fujio, Kenneth Walsh, Kathy K. Griendling

Research output: Contribution to journalArticle

482 Scopus citations

Abstract

Angiotensin II, a hypertrophic/anti-apoptotic hormone, utilizes reactive oxygen species (ROS) as growth-related signaling molecules in vascular smooth muscle cells (VSMCs). Recently, the cell survival protein kinase Akt/protein kinase B (PKB) was proposed to be involved in protein synthesis. Here we show that angiotensin II causes rapid phosphorylation of Akt/PKB (6- ± 0.4-fold increase). Exogenous H2O2 (50-200 μM) also stimulates Akt/PKB phosphorylation (maximal 8- ± 0.2-fold increase), suggesting that Akt/PKB activation is redox-sensitive. Both angiotensin II and H2O2 stimulation of Akt/PKB are abrogated by the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294002 (2(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), suggesting that PI3-K is an upstream mediator of Akt/PKB activation in VSMCs. Furthermore, diphenylene iodonium, an inhibitor of flavin-containing oxidases, or overexpression of catalase to block angiotensin II-induced intracellular H2O2 production significantly inhibits angiotensin II- induced Akt/PKB phosphorylation, indicating a role for ROS in agonist- induced Akt/PKB activation. In VSMCs infected with dominant-negative Akt/PKB, angiotensin II-stimulated [3H]leucine incorporation is attenuated. Thus, our studies indicate that Akt/PKB is part of the remarkable spectrum of angiotensin II signaling pathways and provide insight into the highly organized signaling mechanisms coordinated by ROS, which mediate the hypertrophic response to angiotensin II in VSMCs.

Original languageEnglish (US)
Pages (from-to)22699-22704
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number32
DOIs
StatePublished - Aug 6 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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