A Peculiar Result and a Fanciful Hypothesis Regarding l -Arginine

In the January 2003 issue of this Journal, Chen et al 1 observed that L-arginine supplementation did not affect lesion formation in the hypercholesterolemic apolipoprotein E knockout mice, and it negated the protective effect that iNOS gene deficiency has in this model. Their findings are discordant with those observed in most other hypercholesterolemic models in which the administration of supplemental L-arginine improves vasodilation, increases endothelial synthesis of NO, reduces the generation of superoxide anion, suppresses the activation of oxidant sensitive transcriptional proteins, and reduces monocyte adhesion, infiltration, and lesion formation. [2] 3][4][5][6][7] In most hypercholesterolemic models, L-arginine appears to be rate-limiting for the synthesis of NO. This may be due to increases in plasma asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor), expression of tissue arginase, or NO synthase uncoupling. [8][ [10] Attempting to explain the results of Chen et al, in his editorial Loscalzo 11 proposes the fanciful hypothesis that supplemental L-arginine could increase plasma levels of homocyst(e)ine, a substance known to induce endothelial dysfunction and atherosclerosis. Unfortunately, this hypothesis lacks any mechanistic basis or experimental support. Loscalzo notes correctly that L-arginine is a precursor for guanidinoacetate (GAA), a reaction catalyzed by L-arginine:glycine amidinotransferase (AGAT). The methylation of GAA by S-adenosylmethionine yields creatine and S-adenosylhomocysteine. Loscalzo speculates that supplemental arginine could increase homocysteine by this pathway. However, the article he cites to support his speculation revealed that GAA, not L-arginine, increased homocysteine levels in Sprague-Dawley rats. 12 Notably, GAA markedly suppressed the activity of AGAT. The negative regulation of AGAT activity by GAA would inhibit the conversion of L-arginine to GAA. Thus, the cited article does not provide evidence that L-arginine supplementation would increase homocysteine levels.