Homocysteine augments cytokine-induced chemokine expression in human vascular smooth muscle cells: implications for atherogenesis.
Hyperhomocysteinemia is an independent risk factor for atherosclerosis and atherothrombosis. While in vitro studies have revealed a number of homocysteine-mediated alterations in the thromboregulatory properties of endothelial cells, comparatively little is known about homocysteine-modulated smooth muscle cell function. We observed that exposure of human aortic smooth muscle cells to pathophysiologically relevant concentrations of homocysteine results in concentration-dependent increases in cytokine-induced MCP-1 and IL-8 secretion. RNase protection assays revealed that both MCP-1 and IL-8 mRNA concentrations are increased in homocysteine-treated smooth muscle cells when compared to cells activated with cytokines alone. Homocysteine treatment also increased cytosolic-to-nuclear translocation of the p65 and p50 subunits of the Rel/NF-kappaB family of transcription factors but had no effect on AP-1 activation. Cumulatively, these data suggest that homocysteine may increase monocyte recruitment into developing atherosclerotic lesions by upregulating MCP-1 and IL-8 expression in vascular smooth muscle cells.
Desai
A
A
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
Lankford
H A
HA
Warren
J S
JS
D001161:Arteriosclerosis / Q000209:etiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000008:administration & dosage*; D004357:Drug Synergism; D006710:Homocysteine / Q000008:administration & dosage*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications; D007371:Interferon-gamma / Q000008:administration & dosage; D007375:Interleukin-1 / Q000008:administration & dosage; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects
D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D006710:Homocysteine; D007371:Interferon-gamma