Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells

Aguado, A. et al. (2016) Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells. Journal of Hypertension, 34(2), pp. 253-265. (doi:10.1097/hjh.0000000000000801) (PMID:26682942)

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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 H2O2 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.

Item Type:Articles
Additional Information:The study was supported by MINECO (SAF2012–36400), ISCIII-Fondo Europeo de Desarrollo Regional (FEDER) (RD12/0042/0024, RD12/0042/0053, PI13/01488 and PI12/01952), COST BM1301, and NIH (R01CA134609). A.A. and A.M.B. were supported by a FPI fellowship and the Ramo´n y Cajal Program (RYC-2010–06473), respectively. R.M.T. was supported through grants from the Canadian Institutes of Health Research and the British Heart Foundation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Briones, Dr Ana and Touyz, Professor Rhian
Authors: Aguado, A., Fischer, T., Rodríguez, C., Manea, A., Martínez-González, J., Touyz, R. M., Hernanz, R., Alonso, M. J., Dixon, D. A., Briones, A. M., and Salaices, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hypertension
Publisher:Wolters Kluwer
ISSN:0263-6352
ISSN (Online):1473-5598

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