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Homocysteine induces VCAM-1 gene expression through NF-κB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants

Homocysteine induces VCAM-1 gene expression through NF-κB and NAD(P)H oxidase activation:... Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-κB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans -resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-κB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 µmol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-κB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-κB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IκB-α and IκB- by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47 phox subunit. NF-κB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by >60% at 10 –6 mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-κB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage. atherosclerosis; endothelial activation; homocysteine; gene expression; inflammation; nuclear factor-κB Address for reprint requests and other correspondence: R. De Caterina, Institute of Cardiology, "G. d'Annunzio" Univ.-Chieti, c/o Ospedale S. Camillo de Lellis, Via Forlanini, 50, I-66100 Chieti, Italy http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Heart and Circulatory Physiology The American Physiological Society

Homocysteine induces VCAM-1 gene expression through NF-κB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants

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References (79)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0363-6135
eISSN
1522-1539
DOI
10.1152/ajpheart.00432.2007
pmid
17586618
Publisher site
See Article on Publisher Site

Abstract

Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-κB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans -resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-κB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 µmol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-κB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-κB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IκB-α and IκB- by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47 phox subunit. NF-κB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by >60% at 10 –6 mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-κB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage. atherosclerosis; endothelial activation; homocysteine; gene expression; inflammation; nuclear factor-κB Address for reprint requests and other correspondence: R. De Caterina, Institute of Cardiology, "G. d'Annunzio" Univ.-Chieti, c/o Ospedale S. Camillo de Lellis, Via Forlanini, 50, I-66100 Chieti, Italy

Journal

AJP - Heart and Circulatory PhysiologyThe American Physiological Society

Published: Oct 1, 2007

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