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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2344    most recent 00432.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Carluccio, M. A. Articles by De Caterina, R. Search for Related Content PubMed PubMed Citation Articles by Carluccio, M. A. Articles by De Caterina, R.

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

¹Consiglio Nazionale delle Ricerca Institute of Clinical Physiology and ²Department of Biology, University of Lecce, Lecce; and ³Institute of Cardiology, "G. d'Annunzio" University, Chieti, Italy

Submitted 7 April 2007 ; accepted in final form 18 June 2007

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-B-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-B-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-B motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-B activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IB- and IB- 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-B 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-B. 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-B

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