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Am J Physiol Cell Physiol 284: C1039-C1047, 2003; doi:10.1152/ajpcell.00464.2001
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Vol. 284, Issue 4, C1039-C1047, April 2003

Ikappa Balpha -dependent regulation of low-shear flow-induced NF-kappa B activity: role of nitric oxide

Sumathy Mohan1, Masao Hamuro1, George P. Sorescu5, Koichi Koyoma1, Eugene A. Sprague2, Hanjoong Jo5, Anthony J. Valente3, Thomas J. Prihoda1, and Mohan Natarajan4

Departments of 1 Pathology, 2 Radiology, 3 Medicine, and 4 Radiation Oncology, University of Texas Health Science Center, San Antonio, Texas 78229; and 5 Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Atlanta, Georgia 30322

We have investigated the role of inhibitor kappa Balpha (Ikappa Balpha ) in the activation of nuclear factor kappa B (NF-kappa B) observed in human aortic endothelial cells (HAEC) undergoing a low shear stress of 2 dynes/cm2. Low shear for 6 h resulted in a reduction of Ikappa Balpha levels, an activation of NF-kappa B, and an increase in kappa B-dependent vascular cell adhesion molecule 1 (VCAM-1) mRNA expression and endothelial-monocyte adhesion. Overexpression of Ikappa Balpha in HAEC attenuated all of these shear-induced responses. These results suggest that downregulation of Ikappa Balpha is the major factor in the low shear-induced activation of NF-kappa B in HAEC. We then investigated the role of nitric oxide (NO) in the regulation of Ikappa Balpha /NF-kappa B. Overexpression of endothelial nitric oxide synthase (eNOS) inhibited NF-kappa B activation in HAEC exposed to 6 h of low shear stress. Addition of the structurally unrelated NO donors S-nitrosoglutathione (300 µM) or sodium nitroprusside (1 mM) before low shear stress significantly increased cytoplasmic Ikappa Balpha and concomitantly reduced NF-kappa B binding activity and kappa B-dependent VCAM-1 promoter activity. Together, these data suggest that NO may play a major role in the regulation of Ikappa Balpha levels in HAEC and that the application of low shear flow increases NF-kappa B activity by attenuating NO generation and thus Ikappa Balpha levels.

low shear stress; inhibitor kappa B; endothelial nitric oxide synthase; nuclear factor-kappa B


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