NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II

• DOI: 10.1091/mbc.e10-12-0971
• Publication Date: 2011-10-01T04:22:33Z
• Authors: Isabel Diebold; Andreas Petry; Maximilian Burger; John Hess; Agnes Görlach
• Keywords: NOX4; Urotensin II; MMP2

The vasoactive peptide urotensin-II (U-II) has been associated with vascular remodeling in different cardiovascular disorders. Although U-II can induce reactive oxygen species (ROS) by the NADPH oxidase NOX4 and stimulate smooth muscle cell (SMC) proliferation, precise mechanisms linking to processes remain unclear. Forkhead Box O (FoxO) transcription factors have redox signaling control of proliferation apoptosis. We thus hypothesized that FoxOs are involved SMC response toward NOX4. found stimulated FoxO activity identified matrix metalloproteinase-2 (MMP2) as target gene FoxO3a. FoxO3a activation was preceded NOX4-dependent phosphorylation c-Jun NH(2)-terminal kinase 14-3-3 decreased interaction its inhibitor 14-3-3, allowing MMP2 transcription. Functional studies FoxO3a-depleted SMCs FoxO3a(-/-) mice showed important for basal U-II-stimulated outgrowth, whereas treatment an blocked these responses. Our study new activators FoxO3a, a novel this pathway promotes growth. may contribute progression diseases remodeling.