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(Circulation. 1997;95:311-312.)
© 1997 American Heart Association, Inc.

Articles

Arginine: A New Therapy for Atherosclerosis?

John P. Cooke, MD, PhD; Philip S. Tsao, PhD

the Stanford (Calif) School of Medicine.

Correspondence to Philip S. Tsao, PhD, Division of Cardiovascular Medicine, Stanford School of Medicine, 300 Pasteur Dr, CVRB, Stanford, CA 94305-5246.

Key Words: Editorials • atherosclerosis • arginine

	Introduction

Top Introduction References

 
In this issue of Circulation, Aji et al¹ provide compelling evidence for an antiatherogenic effect of dietary arginine supplementation. To examine the effect of arginine on the progression of atherosclerosis, they used a murine model in which the LDL receptor is disrupted by homologous recombination. This results in a deficiency of functional LDL receptors much like that observed in familial hypercholesterolemia in humans. In response to a high-fat diet, these animals develop severe hypercholesterolemia, xanthoma formation, and accelerated atherosclerosis.² In this study, dietary arginine supplementation markedly reduced the development of intimal lesions. Furthermore, xanthoma formation was abolished. These effects of arginine were probably due to its conversion to NO, because they were abrogated by coadministration of nitro-L-arginine, an antagonist of NOS.

This article adds further weight to the accumulating evidence that dietary supplementation of arginine inhibits atherogenesis. The present investigation also supports the hypothesis that arginine exerts its effects by enhancing the synthesis of NO.

Arginine is a semiessential amino acid that, among other functions, also serves as the substrate for the enzyme NOS, which converts arginine to citrulline and NO.³ Normally, arginine is not rate-limiting in this reaction; the K_m for NOS is in the micromolar range,⁴ whereas intracellular levels of arginine are in the millimolar range. Under certain conditions, however, arginine administration can enhance the synthesis of NO. In hypercholesterolemic rabbits and humans, endothelium-dependent vasodilation due to NO is impaired; administration of arginine restores endothelium-dependent vasodilation.^{5 6 7 8} Using chemiluminescent techniques, we have shown that this effect of arginine supplementation is associated with an increased synthesis of NO by the vascular endothelium.⁸ Recent work by Bode-Boger and colleagues⁹ has revealed a likely mechanism for the enhancement of NO synthesis by arginine supplementation. These investigators discovered higher circulating levels of ADMA in hypercholesterolemic rabbits. ADMA is an endogenous competitive inhibitor of NOS.¹⁰ Elevated levels of ADMA have been shown to inhibit endothelium-dependent vasodilation; this effect is reversed by exogenous L-arginine.¹⁰ Recently, we found that ADMA levels are elevated by twofold in young hypercholesterolemic humans (unpublished observations); this finding may explain our earlier study revealing that arginine administration restores endothelium-dependent vasodilation in this population.⁶

Endothelium-derived NO not only is a potent vasodilator but also inhibits the adherence of circulating blood elements to the vessel wall and suppresses the proliferation of vascular smooth muscle cells.^{11 12 13} On the basis of these in vitro observations, several years ago we tested the hypothesis that endothelium-derived NO may be an endogenous antiatherogenic molecule.

In 1992, we published the first evidence that chronic administration of supplemental dietary arginine restores endothelium-mediated NO-dependent vasodilation in hypercholesterolemic rabbits and markedly inhibits intimal lesion formation.¹⁴ Since that time, a number of studies have revealed that administration of the NO precursor inhibits, whereas NOS antagonists accelerate, monocyte adhesion and accumulation in the vessel wall of hypercholesterolemic animal models.^{8 15 16} A recent study found a beneficial effect of dietary arginine in male but not female hypercholesterolemic rabbits.¹⁶ However, in the present study by Aji et al,¹ there was no sex difference in the antiatherogenic effect of arginine. The difference between these two studies may be related to species-specific responses to hypercholesterolemia.

The mechanism by which arginine-NO synthesis inhibits atherogenesis has not been entirely elucidated and is probably multifactorial. NO can inhibit monocyte adhesion to the endothelium with a rapid onset of action that is probably mediated by cGMP modulation of adhesion signaling.^{12 17} However, NO also inhibits the expression of endothelial proteins, such as VCAM-1 and MCP-1, that are putatively involved in monocyte adhesion to the endothelium.^{18 19 20} Recent studies from our laboratory and others implicate the existence of an oxidant-sensitive transcriptional pathway that activates the expression of VCAM-1 and MCP-1.^{18 19 20 21} In animal models, we find that a number of metabolic alterations that predispose to atherogenesis (such as hypercholesterolemia, diabetes mellitus, or hypertension) are associated with endothelial elaboration of superoxide anion (unpublished studies). The elaboration of superoxide anion is associated with activation of the transcriptional protein NF-B, induced expression of VCAM-1 and MCP-1, and enhanced endothelial adhesiveness for monocytes. We speculate that this oxidant-sensitive transcriptional pathway may be the final common pathway by which a variety of risk factors initiate atherogenesis. The existence of an oxidant-sensitive transcriptional pathway invokes the existence of factors to regulate its activation. A few laboratories have recently provided evidence that NO acts as a brake on the activity of this oxidant-sensitive transcriptional pathway.^{19 20 21} We find that in cultured human aortic endothelial cells exposed to oxidized lipoprotein or cytokines, endogenous NO or exogenous NO donors inhibit endothelial elaboration of superoxide anion, reduce the activity of NF-B, suppress the stimulated expression of VCAM-1 and MCP-1, and reduce endothelial adhesiveness for monocytes. NO may exert these effects in part by inhibiting the generation of superoxide anion by oxidative enzymes.²²

In the hypercholesterolemic rabbit, the progression of intimal lesion formation appears to be strongly influenced by the level of vascular NO activity. Indeed, enhancement of vascular NO synthesis may even induce regression of preexisting lesions.²³ Preliminary studies from our laboratory indicate that this NO-induced regression is mediated in part by accelerated apoptosis of foam cells within the lesion.

To summarize, in the present study and in other experimental models of atherosclerosis, the weight of evidence favors the hypothesis that supplemental dietary arginine exerts an antiatherogenic effect. This effect of arginine is largely due to its metabolism to NO. The accumulated data suggest that enhancement of the NOS pathway may be a novel therapeutic strategy in the treatment of atherosclerosis.

	Selected Abbreviations and Acronyms

 

ADMA = asymmetric dimethyl arginine MCP = monocyte chemotactic protein NF = nuclear factor NO = nitric oxide NOS = nitric oxide synthase VCAM = vascular cell adhesion molecule

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

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