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Cardiovascular Research Advance Access first published online on January 6, 2009
This version [Corrected Proof] published online on January 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvn360
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress

Daniel E. Conway1, Yumiko Sakurai1, Daiana Weiss2, J. David Vega3, W. Robert Taylor1,2, Hanjoong Jo1,2, Suzanne G. Eskin1, Craig B. Marcus4 and Larry V. McIntire1,*

1 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University School of Medicine, 313 Ferst Drive, Suite 2116, Atlanta, GA 30332-0535, USA
2 Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
3 Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
4 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA

* Corresponding author. Tel: +1 404 894 5057; fax: +1 404 385 5028. E-mail address: larry.mcintire{at}bme.gatech.edu

Aims: CYP1A1 and CYP1B1, members of the cytochrome P450 protein family, are regulated by fluid shear stress. This study describes the effects of duration, magnitude and pattern of shear stress on CYP1A1 and CYP1B1 expressions in human endothelial cells, towards the goal of understanding the role(s) of these genes in pro-atherogenic or anti-atherogenic endothelial cell functions.

Methods and results: We investigated CYP1A1 and CYP1B1 expressions under different durations, levels, and patterns of shear stress. CYP1A1 and CYP1B1 mRNA, protein, and enzymatic activity were maximally up-regulated at ≥24 h of arterial levels of shear stress (15–25 dynes/cm2). Expression of both genes was significantly attenuated by reversing shear stress when compared with 15 dynes/cm2 steady shear stress. Small interfering RNA knockdown of CYP1A1 resulted in significantly reduced CYP1B1 and thrombospondin-1 expression, genes regulated by the aryl hydrocarbon receptor (AhR). Immunostaining of human coronary arteries showed constitutive CYP1A1 and CYP1B1 protein expressions in endothelial cells. Immunostaining of mouse aorta showed nuclear localization of AhR and increased expression of CYP1A1 in the descending thoracic aorta, whereas reduced nuclear localization of AhR and attenuated CYP1A1 expression were observed in the lesser curvature of the aortic arch.

Conclusion: CYP1A1 and CYP1B1 gene and protein expressions vary with time, magnitude, and pattern of shear stress. Increased CYP1A1 gene expression modulates AhR-regulated genes. Based on our in vitro reversing flow data and in vivo immunostained mouse aorta, we suggest that increased expression of both genes reflects an anti-atherogenic endothelial cell phenotype.

KEYWORDS CYP1A1; CYP1B1; Shear stress; Vascular endothelial cell; Aryl hydrocarbon receptor

Time for primary review: 26 days


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