title: NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II.
abstract: 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, the precise mechanisms linking U-II to vascular remodeling processes remain unclear. Forkhead Box O (FoxO) transcription factors have been associated with redox signaling and control of proliferation and apoptosis. We thus hypothesized that FoxOs are involved in the SMC response toward U-II and NOX4. We found that U-II and NOX4 stimulated FoxO activity and identified matrix metalloproteinase-2 (MMP2) as target gene of FoxO3a. FoxO3a activation by U-II was preceded by NOX4-dependent phosphorylation of c-Jun NH(2)-terminal kinase and 14-3-3 and decreased interaction of FoxO3a with its inhibitor 14-3-3, allowing MMP2 transcription. Functional studies in FoxO3a-depleted SMCs and in FoxO3a(-/-) mice showed that FoxO3a was important for basal and U-II-stimulated proliferation and vascular outgrowth, whereas treatment with an MMP2 inhibitor blocked these responses. Our study identified U-II and NOX4 as new activators of FoxO3a, and MMP2 as a novel target gene of FoxO3a, and showed that activation of FoxO3a by this pathway promotes vascular growth. FoxO3a may thus contribute to progression of cardiovascular diseases associated with vascular remodeling.
authors.affiliation: Experimental and Molecular Pediatric Cardiology, Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, 80636 Munich, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Diebold
authors.forename: Andreas
authors.initials: A
authors.lastname: Petry
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: John
authors.initials: J
authors.lastname: Hess
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000254:growth & development / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014579:Urotensins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D061965:Matrix Metalloproteinase Inhibitors; D017382:Reactive Oxygen Species; D014579:Urotensins; C482982:YWHAB protein, human; C029677:urotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2