Cardiovascular Research Advance Access first published online on December 7, 2007
This version [Corrected Proof] published online on January 23, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm095
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Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells
1 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
2 Department of Pathology, Nihon University School of Medicine, Tokyo, Japan
* Corresponding author. Tel: +81 92 642 6082; fax: +81 92 642 6084. E-mail address: ymiwa{at}clipharm.med.kyushu-u.ac.jp
Aims: We investigated the mechanisms of shear stress (SS)-induced activation of cytochrome P450 (CYP) 1A1 and cell cycle arrest with regard to the role of the aryl hydrocarbon receptor (AhR), since AhR mediates the expression of CYP1A1 induced by polycyclic aromatic hydrocarbons (PAHs) and is thought to be involved in the regulation of cell growth and differentiation.
Methods and results: Human umbilical vein endothelial cells (ECs) were exposed to laminar SS and thereafter collected to evaluate the expression, activity, and transcription of CYP1A1 and the expression of AhR and cell cycle-related proteins. A physiological level of laminar SS (15 dynes/cm2) markedly increased the expression level and enzymatic activity of CYP1A1. SS stimulated CYP1A1 promoter activity without influencing mRNA stability. Loss of two functional xenobiotic response elements (XREs) in the 5'-flanking region of the CYP1A1 gene suppressed the SS-induced transcription of CYP1A1. Laminar SS stimulated the expression and nuclear translocation of AhR. 
-Naphthoflavone, an AhR antagonist, and a small interfering RNA (siRNA) for AhR significantly suppressed SS-induced CYP1A1 expression. The siRNA also abolished SS-induced cell cycle arrest, the expression of the cyclin-dependent kinase inhibitor p21Cip1, and dephosphorylation of retinoblastoma protein.
Conclusion: Laminar SS stimulated the transcription of CYP1A1 through the activation of AhR in a way that is similar to the effects of PAHs. AhR was also involved in cell cycle arrest induced by SS. Our results suggest that sustained activation of AhR exposed to blood flow plays an important role in the regulation of EC functions.
KEYWORDS Aryl hydrocarbon receptor; CYP1A1; Shear stress; Cell cycle; Endothelial cell
Time for primary review: 29 days
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