Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells.
Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells.
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DOI：
10.1097/hjh.0000000000000801
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发表时间：
2016-02
影响因子：
4.9
通讯作者：
Salaices M
中科院分区：
文献类型：
--
作者：
Aguado A;Fischer T;Rodríguez C;Manea A;Martínez-González J;Touyz RM;Hernanz R;Alonso MJ;Dixon DA;Briones AM;Salaices M
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 HuR is implicated in post-transcriptional regulation of gene expression; however, its role regulating NOX is unknown. We investigated transcriptional and post-transcriptional mechanisms underlying angiotensinII (AngII) and interleukin-1β (IL-1β) regulation of NOX-1 and NOX-4 in VSMC and their implications in cell migration. Rat and human VSMC were stimulated with AngII (0.1 μM) 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. 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 down-regulation. 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. 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.
