15704254

pubmed:Citation

8

Previous studies have shown that L-arginine (L-Arg) administration to apoE-/-/iNOS-/- double knockout mice (dKO) on a Western diet paradoxically results in an increase in atherosclerotic lesion size. We hypothesized that the potential beneficial effects of L-Arg could be offset, in part, by the byproducts of L-Arg catabolism, especially the atherogenic risk factor, homocysteine. In the kidney, L-Arg is converted to L-ornithine and guanidinoacetate (GAA) by L-arginine-glycine amidinotransferase. The efficient transmethylation of GAA by an S-adenosyl-methionine (SAM)-dependent methyltransferase in liver yields creatine and S-adenosylhomocysteine (SAH), which is readily hydrolyzed to homocysteine and adenosine. We, therefore, measured total plasma homocysteine in the dKO mice and control mice. We found that L-Arg supplementation caused a 37% increase in total plasma homocysteine (tHcy) levels in dKO mice compared to controls not treated with L-Arg (5.2+/-2.2 vs 3.8+/-1.5 microM Hcy, p<0.04). In a liver cell line, HepG2, addition of 10 and 50 microM GAA in the presence of 50 microM L-methionine (L-Met) increased tHcy production by approximately 1.47 (p<0.0001) and 2.3-fold (p<0.0001), respectively. In the presence of additional 100 microM L-Met, baseline homocysteine production was elevated by 20% (p<0.005), and 10 and 50 microM GAA augmented homocysteine production by an additional 1.88- (p<0.0001) and 3.4-fold (p<0.001), respectively, compared with 50 microM L-Met. These data suggest that increased concentrations of a methyl acceptor, such as L-Arg-derived GAA, drives SAM-dependent-methylation and consequent homocysteine formation. Furthermore, L-Met levels can also influence homocysteine production likely by regulating the synthesis of the methyl donor SAM. Epidemiological studies have suggested that homocysteine is a graded risk factor. In animal models, modestelevations of homocysteine can cause endothelial dysfunction and augment atherosclerosis. Our data suggest that L-arginine supplementation may contribute to vascular injury and atherogenesis under some circumstances by elevating homocysteine levels.

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0145-5680

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903-9

pubmed-meshheading:15704254-Animals, pubmed-meshheading:15704254-Apolipoproteins E, pubmed-meshheading:15704254-Arginine, pubmed-meshheading:15704254-Arteriosclerosis, pubmed-meshheading:15704254-Cell Line, pubmed-meshheading:15704254-Dietary Supplements, pubmed-meshheading:15704254-Dose-Response Relationship, Drug, pubmed-meshheading:15704254-Glycine, pubmed-meshheading:15704254-Homocysteine, pubmed-meshheading:15704254-Methionine, pubmed-meshheading:15704254-Methylation, pubmed-meshheading:15704254-Mice, pubmed-meshheading:15704254-Mice, Knockout, pubmed-meshheading:15704254-Models, Biological, pubmed-meshheading:15704254-Nitric Oxide Synthase, pubmed-meshheading:15704254-Nitric Oxide Synthase Type II, pubmed-meshheading:15704254-Ornithine, pubmed-meshheading:15704254-Risk Factors, pubmed-meshheading:15704254-Time Factors

L-arginine increases plasma homocysteine in apoE-/-/iNOS-/- double knockout mice.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural