Dexamethasone Upregulates Nox1 Expression in Vascular Smooth Muscle Cells

Background/Aim: It has been demonstrated that dexamethasone-induced hypertension can be prevented by the NADPH oxidase inhibitor apocynin. The effect of dexamethasone on NADPH oxidase, however, is unknown. The present study was conducted to investigate the effect of dexamethasone on the gene expression of Nox1, the major NADPH oxidase isoform in vascular smooth muscle cells. Results: Oral treatment of Wistar-Kyoto rats with dexamethasone (0.03 mg/kg/day) for 12 days led to an upregulation of Nox1 mRNA expression in the aorta. In cultured A7r5 rat aortic smooth muscle cells, dexamethasone increased Nox1 mRNA expression in a concentration- and time-dependent manner. The upregulation of Nox1 mRNA expression was completely prevented by the glucocorticoid receptor antagonist mifepristone. The effect of dexamethasone on Nox1 expression was likely to be indirect as it could be largely blocked by cycloheximide, an inhibitor of protein biosynthesis. Dexamethasone increased Nox1 mRNA stability as well as Nox1 transcription. The dexamethasone-induced Nox1 expression was completely prevented by scriptaid, a pan-inhibitor of histone deacetylases (HDAC), indicating a crucial role for HDAC enzymes. In total, A7r5 cells expressed 8 HDAC iso-forms, with HDAC1, 5, 6 and 7 being the most abundant ones. Knockdown of these 4 individual HDAC enzymes did not prevent the effect of dexamethasone on Nox1 expression, although HDAC5 knockdown markedly reduced basal Nox1 expression. Conclusion: Dexamethasone upregulates Nox1 expression in vascular smooth muscle cells. This effect involves the glucocorticoid receptor and HDAC enzymes. (C) 2014 S. Karger AG, Basel