Published online before print November 20, 2003, doi: 10.1161/01.RES.0000108264.67601.2C
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Molecular Medicine |
Hyperhomocysteinemia Activates Nuclear Factor-
B in Endothelial Cells via Oxidative Stress
From the Department of Pharmacology (F.L.S., J.C.W.Y., Y.L.S., K.O), Faculty of Medicine, The University of Hong Kong, and National Centre for Agri-Food Research in Medicine (K.K.W.A-Y., C.W.H.W., Y.L.S., K.O.), Departments of Animal Science and Physiology, University of Manitoba, Canada.
Correspondence to Dr Karmin O, MD, PhD, Laboratory of Integrative Biology, NCARM, St Boniface Hospital Research Centre, R4032, 351 Tache Ave, Winnipeg, Manitoba R2H 2A6, Canada. E-mail karmino{at}sbrc.ca
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-
B (NF-B) activation and homocysteine (Hcy)-induced chemokine expression in vascular smooth muscle cells and macrophages. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-B activation and the underlying mechanism of Hcy-induced NF-B activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-B and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-B activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 µmol/L) activated IB kinases (IKK
and IKKß), leading to phosphorylation and subsequent degradation of IB. As a consequence, NF-B nuclear translocation, enhanced NF-B/DNA binding activity, and increased transcriptional activity occurred. Additional analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with a superoxide anion scavenger (polyethylene glycol-superoxide dismutase) or IB kinase inhibitor (prostaglandin A1) could prevent Hcy-induced activation of IKK kinases and NF-B in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-B activation in the early stages of atherosclerosis in the vascular wall via activation of IB kinases.
Key Words: homocysteine • nuclear factor-B • IB • IB kinase • superoxide
This article has been cited by other articles:
 |
|
 |
|
  H. Stopper, A.-T. Treutlein, U. Bahner, N. Schupp, U. Schmid, A. Brink, A. Perna, and A. Heidland Reduction of the genomic damage level in haemodialysis patients by folic acid and vitamin B12 supplementation Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3272 - 3279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. Mikael and R. Rozen Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-{kappa}B/iNOS Cardiovasc Res, October 1, 2008; 80(1): 151 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-Y. Chang, S.-C. Lu, C.-M. Lee, Y.-J. Chen, T. A. Dugan, W.-H. Huang, S.-F. Chang, W. S.L. Liao, C.-H. Chen, and Y.-T. Lee Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation Circ. Res., April 25, 2008; 102(8): 933 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, C. Jiang, G. Xu, N. Wang, Y. Zhu, C. Tang, and X. Wang Homocysteine Upregulates Resistin Production From Adipocytes In Vivo and In Vitro Diabetes, April 1, 2008; 57(4): 817 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. H. Woo, Y. L. Siow, and K. O Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation J. Biol. Chem., January 18, 2008; 283(3): 1282 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Hwang, C. W. H. Woo, K. K. W. Au-Yeung, Y. L. Siow, T. Y. Zhu, and K. O Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-{kappa}B activation Am J Physiol Renal Physiol, January 1, 2008; 294(1): F236 - F244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Carluccio, M. A. Ancora, M. Massaro, M. Carluccio, E. Scoditti, A. Distante, C. Storelli, and R. De Caterina Homocysteine induces VCAM-1 gene expression through NF-{kappa}B and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2344 - H2354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sahin, F.B. Aksungar, A.E. Topkaya, Z. Yildiz, U.T. Boru, S. Ayalp, and S. Karsidag Increased plasma homocysteine levels in multiple sclerosis Multiple Sclerosis, August 1, 2007; 13(7): 945 - 946. [PDF]
|
|
|
|
 |
|
 C. Prontera, N. Martelli, V. Evangelista, E. D'Urbano, S. Manarini, A. Recchiuti, A. Dragani, C. Passeri, G. Davi, and M. Romano Homocysteine Modulates the CD40/CD40L System J. Am. Coll. Cardiol., June 5, 2007; 49(22): 2182 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Prathapasinghe, Y. L. Siow, and K. O Detrimental role of homocysteine in renal ischemia-reperfusion injury Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1354 - F1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. H. Meng, G. Yang, W. Yang, B. Jiang, L. Wu, and R. Wang Protective Effect of Hydrogen Sulfide on Balloon Injury-Induced Neointima Hyperplasia in Rat Carotid Arteries Am. J. Pathol., April 1, 2007; 170(4): 1406 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rocic, B. Rezk, and P. A. Lucchesi PPAR-{gamma} agonists decrease hyperhomcysteinemia and cardiac dysfunction: new hope for ailing diabetic hearts? Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H26 - H28. [Full Text] [PDF]
|
|
|
|
 |
|
 C. W.H. Woo, Y. L. Siow, and K. O Homocysteine Activates cAMP-response Element Binding Protein in HepG2 Through cAMP/PKA Signaling Pathway Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1043 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Devlin and S. R. Lentz ApoA-I: A Missing Link Between Homocysteine and Lipid Metabolism? Circ. Res., March 3, 2006; 98(4): 431 - 433. [Full Text] [PDF]
|
|
|
|
|
|
O. Postea, F. Krotz, A. Henger, C. Keller, and N. Weiss Stereospecific and Redox-Sensitive Increase in Monocyte Adhesion to Endothelial Cells by Homocysteine Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 508 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Csiszar, M. Ahmad, K. E. Smith, N. Labinskyy, Q. Gao, G. Kaley, J. G. Edwards, M. S. Wolin, and Z. Ungvari Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype Am. J. Pathol., February 1, 2006; 168(2): 629 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tan, X. Jiang, F. Yang, Z. Li, D. Liao, J. Trial, M. J. Magera, W. Durante, X. Yang, and H. Wang Hyperhomocysteinemia inhibits post-injury reendothelialization in mice Cardiovasc Res, January 1, 2006; 69(1): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Csiszar, K. E. Smith, A. Koller, G. Kaley, J. G. Edwards, and Z. Ungvari Regulation of Bone Morphogenetic Protein-2 Expression in Endothelial Cells: Role of Nuclear Factor-{kappa}B Activation by Tumor Necrosis Factor-{alpha}, H2O2, and High Intravascular Pressure Circulation, May 10, 2005; 111(18): 2364 - 2372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. H. Woo, Y. L. Siow, G. N. Pierce, P. C. Choy, G. Y. Minuk, D. Mymin, and K. O Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E1002 - E1010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jaramillo, M. Godbout, and M. Olivier Hemozoin Induces Macrophage Chemokine Expression through Oxidative Stress-Dependent and -Independent Mechanisms J. Immunol., January 1, 2005; 174(1): 475 - 484. [Abstract] [Full Text] [PDF]
|
|