Mild Hyperhomocysteinemia Induced by Feeding Rats Diets Rich in Methionine or Deficient in Folate Promotes Early Atherosclerotic Inflammatory Processes

Abstract

High homocysteine levels in vitro promote the expression of inflammatory agents responsible for atherogenesis. We investigated the long-term effects of elevated plasma homocysteine on the expression of inflammatory molecules and attempted to elucidate their mechanisms. Male Sprague-Dawley rats (n = 36) were randomly divided into 3 groups, which received the control AIN-93G diet, the control diet plus 10 g/kg of L-methionine, or that diet without folate (0 m/kg) for 14 wk. Mild hyperhomocysteinemia was then induced in both experimental groups. The mildly hyperhomocysteinemic rats had markedly increased expression of intracellular adhesion molecule-1 (ICAM-1) in the aorta and elevated serum levels of monocyte chemoattractant protein-1 (MCP-1), compared to the control rats. The activation of nuclear factor kappaB and formation of nitrotyrosine in the aorta were greater in rats with mild hyperhomocysteinemia than in control rats. Serum levels of malonyldialdehyde (MDA) were higher in mildly hyperhomocysteinemic rats than in control rats. These results suggest that the oxidative stress resulting from elevated plasma homocysteine stimulates the activation of nuclear factor kappaB, and consequently increases the expression of the inflammatory factors in vivo. Such an effect may contribute to atherogenesis by enhancing the inflammatory response of the vascular endothelium.

Stereospecific and Redox-Sensitive Increase in Monocyte Adhesion to Endothelial Cells by Homocysteine

“…36 Increased activation of NF-B associated with increased expression of ICAM-1 has recently been shown in aortas of mildly hyperhomocysteinemic rats, but not in controls. 37 This confirms the relevance of our findings for the in vivo situation.Elevated Hcy levels are associated with increased vascular superoxide output and vascular oxidant stress. This effect is specific for Hcy and does not occur with other lowmolecular-weight thiols and is stereospecific for the naturally occurring L-isoform of Hcy.…”

Critical evaluation of normotensive rats as models for hypercholesterolaemia-induced atherosclerosis

“…Therefore, the above findings might suggest that diet-induced hypercholesterolaemia led to arterial wall inflammatory response of mild degree. In the same way, mild hyperhomocysteinaemia induced early atherosclerotic inflammatory process of the vascular endothelium in Sprague-Dawley rats (Zhang et al, 2004). However, such a mild arterial inflammatory response was not associated with inflammatory liver response.…”

In Vivo Metabolism of l-Methionine in Mice: Evidence for Stereoselective Formation of Methionine-d-Sulfoxide and Quantitation of Other Major Metabolites

“…Liver Met levels were not measured directly in these cases, but such high plasma Met concentrations may indicate high liver Met levels as well. Because high levels of Met have been implicated in cholestasis, cirrhosis, aminoacidemia, hypoglycemia, atherogenesis, and/or death (Shinozuka et al, 1971;Regina et al, 1993;Moss et al, 1999;Halsted et al, 2002;Zhang et al, 2004), FMO3 S-oxidation of Met may be important in overall Met metabolism and toxicity.…”