Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 6, 2009
Cardiovascular Research, doi:10.1093/cvr/cvn360
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Expression of CYP1A1 and CYP1B1 in human endothelial cells: Regulation by fluid shear stress
1 Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/ Emory University School of Medicine, Atlanta, Georgia, USA
2 Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA
3 Department of Surgery, Emory University School of Medicine, Atlanta, Georgia USA
4 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA
Corresponding author: Larry V. McIntire, Ph.D., Department of Biomedical Engineering Georgia Institute of Technology, 313 Ferst Drive, Suite 2116, Atlanta, Georgia 30332-0535 Tel: (404) 894-5057 Fax: (404) 385-5028 E-mail: larry.mcintire{at}bme.gatech.edu
Aim: 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 expression in human endothelial cells, toward 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 expression under different durations, levels, and patterns of shear stress. CYP1A1 and CYP1B1 mRNA, protein, and enzymatic activity were maximally up-regulated at equal to or greater than 24 hours of arterial levels of shear stress (15-25 dynes/cm2). Expression of both genes was significantly attenuated by reversing shear stress as compared to 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 expression 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.
Conclusions: 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.
Time for primary review: 26 Days
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  R. De Caterina and R. Madonna Cytochromes CYP1A1 and CYP1B1: new pieces in the puzzle to understand the biomechanical paradigm of atherosclerosis Cardiovasc Res, March 1, 2009; 81(4): 629 - 632. [Full Text] [PDF]
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