Published online before print August 28, 2006, doi: 10.1161/01.HYP.0000240630.65726.19
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(Hypertension. 2006;48:E15.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Response to Does Arginase Activity In Vitro Represent That In Vivo?
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md
We thank Drs Zhang and Kaye1 for their comments. We certainly agree that transgenic models are important in evaluating the role of arginase in pathophysiologic conditions. Currently, arginase inhibitors are available and have been used by investigators to assess the role of arginase in cardiovascular physiology and pathophysiology. However, isoform-specific inhibitors (arginase I versus arginase II) would be helpful in determining the role of these 2 isoforms in the biology of reciprocal NO synthase (NOS) regulation and their role in specific disease processes. We, however, respectfully disagree with Drs Zhang and Kaye1 with regard to the absence of arginase activity in endothelial cells. The article quoted by the authors2 supports the idea that endothelial-derived relaxing factor (EDRF) from endothelial cells is limited by L-arginine and is inhibited by L-glutamine, a concept with which we completely agree. However, no direct measure of either arginase activity or expression was performed. In addition, the recent literature is now replete with articles demonstrating arginase expression in both blood vessels and primary endothelial cell culture.3 Moreover, upregulation of endothelial arginase contributes to impaired NO signaling in several disease processes, including hypertension, erectile dysfunction, atherosclerosis, and aging.4
Drs Zhang and Kaye1 interpret the arginine paradox to mean "that extracellular arginine is principally used by endothelial eNOS to produce NO." We contend that this definition is overly restrictive, and the current, widely accepted interpretation of this paradox encompasses several explanations for eNOS substrate limitation in the setting of apparent adequate (given the Michaelis constant of endothelial NOS [eNOS] for L-arginine) and, indeed, excess L-arginine. In certain pathophysiologic circumstances, for example, atherosclerosis, an increase in extracellular L-arginine may indeed enhance eNOS activity. However, it is clear that NOS activity is also dependent on pools of L-arginine that are distinct from those that are exchangeable with extracellular L-arginine via the CAT transporter. This concept is central to the broader interpretation of the arginine paradox. Simon et al5 have clearly demonstrated in endothelial cells that there are 3 distinct pools of L-arginine: the first, pool I, is regulated by the CAT transporter. In contrast, pool II is accessible to eNOS but is not freely exchangeable with extracellular L-arginine (or L-lysine). Subpool IIA can be depleted by neutral amino acids and results from the recycling of citrulline. In contrast, subpool IIB results from protein breakdown and is not responsive to either cationic or neutral amino acids. Because arginase uses this pool, it is reasonable to suggest that it is this pool, regulated by arginase, that is modulating local concentration of L-arginine and thereby eNOS-dependent NO release. Suffice to say that all of the explanations suggest a dynamic spatial confinement of eNOS, endogenous NOS inhibitors, as well as distinct pools of L-arginine, which we and others have demonstrated to be regulated by arginase.
We agree that the conditions in vitro may not mimic the conditions in vivo and that, as a general concept, enzyme activity and inhibition have the potential to be altered by the experimental conditions. However, arginase can, indeed, be inhibited using specific inhibitors in vivo. Furthermore, in vivo inhibition can modulate vascular endothelial function and blood pressure.6 In closing, the emerging concept of eNOS uncoupling encompasses both cofactor and/or substrate depletion.4 Arginase upregulation and L-arginine use resulting in limited L-arginine bioavailability to eNOS is but one specific example of the broader concept.
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Zhang W, Kaye DM. Does arginase activity in vitro represent that in vivo? Hypertension. 2006; 48: e14.[Medline] [Order article via Infotrieve]
2. Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci U S A. 1990; 87: 612–616.
3. Chicoine LG, Paffett ML, Young TL, Nelin LD. Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2004; 287: L60–L68.
4. Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: From marvel to menace. Circulation. 2006; 113: 1708–1714.
5. Simon A, Plies L, Habermeier A, Martine U, Reining M, Closs EI. Role of neutral amino acid transport and protein breakdown for substrate supply of nitric oxide synthase in human endothelial cells. Circ Res. 2003; 93: 813–820.
6. Demougeot C, Prigent-Tessier A, Marie C, Berthelot A. Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens. 2005; 23: 971–978.[Medline] [Order article via Infotrieve]
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