Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells. Issue 2 (February 2016)

• Record Type: Journal Article
• Authors: Aguado, Andrea; Fischer, Thierry; Rodríguez, Cristina; Manea, Adrian; Martínez-González, José; Touyz, Rhian M.; Hernanz, Raquel; Alonso, M. Jesús; Dixon, Dan A.; Briones, Ana M.; Salaices, Mercedes
• Is Part Of: Journal of hypertension. Volume 34:Issue 2(2016:Feb.)
• Publication Date: 2016-02
• Subjects: angiotensin II -- cell migration -- Hu antigen R -- interleukin-1β -- NADPH oxidase -- vascular smooth muscle cells; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000000801
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: NOX-1 and NOX-4 are key enzymes responsible for reactive oxygen species (ROS) generation in vascular smooth muscle cells (VSMC). The RNA-binding protein Hu antigen R (HuR) is implicated in posttranscriptional regulation of gene expression; however, its role regulating NOX is unknown. We investigated transcriptional and posttranscriptional mechanisms underlying angiotensin II (AngII) and IL-1β regulation of NOX-1 and NOX-4 in VSMC and their implications in cell migration. Methods: Rat and human VSMC were stimulated with AngII (0.1 μmol/l) and/or IL-1β (10 ng/ml). NOX-1 and NOX-4 mRNA and protein levels, NOX-1 and NOX-4 promoter and 3′UTR activities, NADPH oxidase activity, ROS production, and cell migration were studied. Results: IL-1β increased NOX-1 expression, NADPH oxidase activity and ROS production, and decreased NOX-4 expression and H2 O2 production in VSMC. AngII potentiated the IL-1β-mediated induction of NOX-1 expression, NADPH oxidase activity, ROS production, and cell migration. However, AngII did not influence IL-1β-induced NOX-4 downregulation. AngII + IL-1β interfered with the decay of NOX-1 mRNA and promoted HuR binding to NOX-1 mRNA. Moreover, HuR blockade reduced NOX-1 mRNA stability and AngII + IL-1β-induced NOX-1 mRNA levels. IL-1β decreased NOX-4 expression through a transcriptional mechanism that involved response elements situated in the proximal promoter. AngII and/or IL-1β-induced cell migration were prevented by NOX-1 and HuR blockade and were augmented by NOX-4 overexpression. Conclusion: In VSMC HuR-mediated mRNA stabilization is partially responsible for AngII + IL-1β-dependent NOX-1 expression, whereas transcriptional mechanisms are involved in decreased NOX-4 expression induced by IL-1β. NOX4 and HuR regulation of NOX-1 contributes to VSMC migration, important in vascular inflammation and remodeling. Abstract : Supplemental Digital Content is available in the text