(Circulation. 1997;95:553-554.)
© 1997 American Heart Association, Inc.
Articles |
Nitric Oxide: Nature's Naturally Occurring Leukocyte Inhibitor
Jefferson Medical Center, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Allan M. Lefer, PhD, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107.
Key Words: Editorials • atherosclerosis • endothelium • endothelium-derived factors • leukocytes
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Introduction |
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 Top Introduction References |
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The vascular endothelium produces NO, which is basally released at concentrations of about 2 to 20 nmol/L.1 2 This NO diffuses to the subjacent vascular smooth muscle, where it regulates vascular tone.3 4 However, the endothelially derived NO also diffuses to the luminal surface of the endothelium, where it exerts a number of important physiological effects, including (1) scavenging of superoxide radicals,5 6 (2) inhibition of platelet adherence and aggregation,7 8 (3) modulation of endothelial layer permeability,9 and (4) attenuation of leukocyte function.10 11 This antileukocyte effect of NO has several components. First, NO markedly attenuates leukocyte rolling along the endothelium by inhibiting the expression of P-selectin on the vascular endothelium.11 12 Second, NO inhibits the firm adherence of leukocytes to the endothelium,11 12 13 partially by inhibition of ICAM-1 and VCAM-1 expression.14 Downregulation of these cell adhesion molecules by NO occurs through inhibition of protein kinase C activation15 and via prevention of the transcription factor nuclear factor-
B, which usually induces expression of the mRNA for these adhesion molecules.14 Third, NO inhibits leukocyte action by inhibiting the cytoassembly of NADPH oxidase,16 thereby attenuating the release of superoxide radicals by activated leukocytes, particularly granulocytes.17 These effects of NO pertain to both neutrophils and monocytes and appear to be relevant to atherosclerosis. Against this backdrop of important effects of physiological concentrations of NO, effective NO levels are decreased in a variety of circulatory disorders, including myocardial ischemia-reperfusion,18 19 20 circulatory shock and trauma,21 22 and hypercholesterolemia and atherosclerosis.23 24 The decrease in NO levels occurs in the early stages of hypercholesterolemia before the development of atherosclerotic plaques23 24 25 26 and is clearly due to reduced basal release of NO27 in addition to diminished agonist-mediated NO release.24 25 26 This reduction in basal NO release leads to an increased leukocyte adherence to the coronary vascular endothelium in hypercholesterolemic rabbits.27 It is therefore not surprising that replacement therapy to restore the NO deficit has been considered in several of these disease states.
NO is a gas (molecular mass, 30 D) that is highly soluble in lipids and thus readily diffuses across cell membranes.28 NO has a half-life of only 10 to 20 seconds in physiological media, including blood.4 29 Since NO avidly combines with the heme moeity of hemoglobin and can become inactivated by its interaction with the superoxide radical, administration of NO to biological systems or the intact organism is difficult. Nevertheless, several strategies are available to overcome a deficit in endogenous NO at the endothelial cell–blood interface. First, one can administer low concentrations of authentic NO either inhaled as a gas30 or infused in solution.31 The limitations of the former are that one can deliver NO only to the pulmonary circulation, and of the latter, that delivery is difficult and one must infuse the NO close to the site of injury. A second approach is the use of NO donors (ie, organic nitrates that release NO in solution). Nitroglycerin and nitroprusside are familiar NO donors used in cardiovascular medicine. Since these agents induce tolerance and require cellular metabolism to release their NO, they are being replaced by newer, more potent NO donors devoid of these difficulties.32 Third, one can transfect the gene for endothelial cell NO synthase (ecNOS, NOSIII33 ) into the vessel wall and restore the ability of the endothelium to produce its own NO. This approach has been used successfully in rat carotid arteries to prevent intimal thickening, which leads to restenosis.34 However, gene therapy is currently impractical other than at the site of a local lesion, and transfection rates are still quite low with the available vectors. Accordingly, this form of NO therapy is not quite ready for patient use at present. The fourth method of restoring the NO deficit is perhaps the most practical, and that is administration of L-arginine, the precursor for NO biosynthesis.35 This approach was used by Adams and coworkers36 in an article published in this issue of Circulation and has several advantages: (1) L-Arginine can be added as a nutritional supplement, (2) it is nontoxic at high doses, and (3) it is relatively inexpensive. L-Arginine has already been shown to improve vasorelaxation to endothelium-dependent vasodilators in humans37 and to diminish endothelial adhesiveness brought about by hypercholesterolemia in rabbits,38 an action related to the antiatherogenic effect of L-arginine.39
Adams et al36 have advanced our knowledge of L-arginine as an antiatherogenic molecule. Using cultured human endothelial cells, they significantly inhibited monocyte adherence to the endothelium over the range of 100 µmol/L to 1 mmol/L L-arginine. This is important for two reasons: (1) Monocytes are the major subtype of leukocyte thought to initiate atherogenesis, developing into transformed macrophages and ultimately becoming foam cells, which form the atherosclerotic plaque; and (2) this process was studied in human monocytes interacting with human endothelial cells. In this setting, L-arginine attenuated monocyte adherence even when the endothelial cells were stimulated with IL-1ß, a cytokine that upregulates several cell adhesion molecules. As an important control, the stereoisomer of L-arginine, D-arginine, which does not lead to NO biosynthesis, did not exert an antiadherent effect. Adams et al36 went on to evaluate some of the important cell adhesion molecules involved in these effects and found that ICAM-1 and VCAM-1 on the endothelial surface were downregulated by L-arginine, ICAM-1 even under stimulation by IL-1ß. These findings are complementary to earlier studies using intravital microscopy showing that NO suppresses P-selectin and ICAM-1 expression in hypercholesterolemia in vivo in the rat mesentery.12 Moreover, L-arginine has been shown to correct the endothelial dysfunction in the coronary microcirculation of hypercholesterolemic patients.17 Those results suggest that the findings of Adams et al36 may be relevant to the intact human circulation. Moreover, the finding that NO suppresses P-selectin expression in hypercholesterolemia provides a mechanism for slowing down leukocytes via selectin-mediated "rolling," enabling ICAM-1 and VCAM-1 to promote firm adhesion of monocytes to the endothelium. By attenuating these changes, L-arginine exerts important effects that could potentially prevent the circulatory sequelae of hypercholesterolemia and atherosclerosis.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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