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(Circulation. 2005;111:2364-2372.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells

Role of Nuclear Factor-B Activation by Tumor Necrosis Factor-, H₂O₂, and High Intravascular Pressure

Anna Csiszar, MD, PhD; Kira E. Smith; Akos Koller, MD, PhD; Gabor Kaley, PhD; John G. Edwards, PhD; Zoltan Ungvari, MD, PhD

From the Department of Physiology, New York Medical College, Valhalla, NY.

Correspondence to Zoltan Ungvari, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail zoltan_ungvari{at}nymc.edu

Received July 29, 2004; revision received December 20, 2004; accepted December 21, 2004.

Background— Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-ß superfamily member cytokine, plays an important role both in vascular development and pathophysiological processes, including endothelial activation that is likely to contribute to the development of coronary atherosclerosis, yet the factors that regulate arterial expression of BMP-2 are completely unknown. We tested the hypothesis that BMP-2 expression in endothelial cells is governed by an H₂O₂ and nuclear factor (NF)-B–dependent pathway that can be activated by both proinflammatory and mechanical stimuli.

Methods and Results— The proinflammatory cytokine tumor necrosis factor (TNF)- induced NF-B activation and elicited significant increases in BMP-2 mRNA and protein in primary coronary arterial endothelial cells and human umbilical vein endothelial cells that were prevented by NF-B inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H₂O₂ also elicited NF-B activation and BMP-2 induction. In organ culture, exposure of rat arteries to high pressure (160 mm Hg) elicited H₂O₂ production, nuclear translocation of NF-B, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF- knockout mice.

Conclusions— Vascular BMP-2 expression can be regulated by H₂O₂-mediated activation of NF-B both by inflammatory stimuli and by high intravascular pressure.

Key Words: free radicals • cytokines • growth factors

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