Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure.
BACKGROUND
Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-beta 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)-kappaBeta-dependent pathway that can be activated by both proinflammatory and mechanical stimuli.


RESULTS
The proinflammatory cytokine tumor necrosis factor (TNF)-alpha induced NF-kappaBeta 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-kappaBeta inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H2O2 also elicited NF-kappaBeta 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-kappaBeta, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-alpha, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF-alpha knockout mice.


CONCLUSIONS
Vascular BMP-2 expression can be regulated by H2O2-mediated activation of NF-kappaBeta both by inflammatory stimuli and by high intravascular pressure.
Csiszar
Anna
A
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Smith
Kira E
KE
Koller
Akos
A
Kaley
Gabor
G
Edwards
John G
JG
Ungvari
Zoltan
Z
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide