doi: 10.1161/01.RES.0000249617.15456.4c
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Editorials |
Roads to Dysfunction
Argininase II Contributes to Oxidized Low-Density Lipoprotein-Induced Attenuation of Endothelial NO Production
From the Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Frankfurt am Main, Germany.
Correspondence to Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes{at}em.uni-frankfurt.de
See related article, pages 951–960
Key Words: statins • arginase • hyperlipidemia • endothelial dysfunction • atherosclerosis • GTPases
Oxidized low-density lipoprotein (oxLDL) is considered to be the strongest proatherogenic lipoprotein. OxLDL is rapidly taken up by endothelial cells and macrophages and via the steps of foam cell formation and cell death, oxLDL eventually accumulates in the lipid core of atherosclerotic plaques.1
The interaction of oxLDL with cells is mediated by several receptors.2 Members of the scavenger receptor family predominate in macrophages,3 whereas endothelial cells mainly take up oxLDL by the lectin-like ox-LDL receptor-1 (LOX-1).4 On binding to LOX-1, oxLDL activates a multitude of signaling cascades involving MAP kinases,5,6 protein kinase C (PKC),7,8 and protein kinase B9 in endothelial cells. The consequence of this cellular activation, is apoptosis and superoxide anion production, the latter originating from the NADPH oxidase and uncoupling of the endothelial NO synthase (eNOS). OxLDL therefore is a strong inducer of endothelial dysfunction, a state in which the endothelium, instead of generating NO, produces superoxide anions. OxLDL also modulates the specific activity of NOS. It increases caveolin I expression and the interaction of NOS with this protein impairs NO production.10 Furthermore, oxLDL modulates PKC activity and expression and this family of kinases has been shown to acutely attenuate eNOS-dependent NO production and to promote eNOS uncoupling during prolonged exposure times.11
Several observations suggest that the supply of eNOS with the substrate L-arginine is impaired in the presence of oxLDL: In hypercholesterolemia, supplementation of L-arginine improves endothelium-dependent relaxation and NO production;12,13 L-arginine also attenuates the development of atherosclerosis,14 and normalizes leukocyte adhesion in hypercholesterolemia.15 Indeed, hypercholesterolemia favors the accumulation of asymmetrical dimethyl-L-arginine (ADMA), a competitive inhibitor to L-arginine of eNOS. ADMA levels are increased in hypercholesterolemic monkeys16 and oxLDL increases the activity of the S-adenosylmethionine-dependent protein arginine methyl-transferases,16 which generate ADMA from L-arginine. Moreover, oxLDL decreases the activity of the ADMA-degrading dimethylarginine dimethylaminohydrolase.17
In this issue of Circulation Research, Ryoo and colleagues identified a new mechanism for oxLDL-induced endothelial dysfunction.18 They demonstrate that oxLDL acutely increases arginase II activity as well as induces arginase II protein expression in human aortic endothelial cells (Figure 1). Arginase catalyzes the hydrolysis of L-arginine to L-ornithin and iso-urea. As iso-urea spontaneously isomerases to urea, this reaction is practically irreversible. Arginine catabolism by arginase is nearly 200-fold greater than that of NOS and thus arginase limits the supply of substrate to NOS. Through this competition for arginine, arginase attenuates NOS-dependent NO production.19 Two arginase isoforms have been identified and differential expression has been noted between cells types and species. In human aortic endothelial cells, arginase II is the predominant isoforms and consequently, the study from Ryoo et al focused on this enzyme.18,19
|
The authors observed that following stimulation with oxLDL arginase II activity is increased in human aortic endothelial cells and this effect was accompanied by an attenuation of NO production, as determined by nitrite measurements. Small interfering RNA directed against arginase II prevented the oxLDL-induced increase in activity and maintained NO production even in the presence of oxLDL. Moreover, in intact rat aortic segments oxLDL attenuated endothelial NO production and this effect was sensitive to the arginase inhibitor (s)-(2-boronoethyl)-L-cysteine. A further analysis revealed that oxLDL increased cellular arginase II activity via 2 different mechanisms: An acute stimulation of the specific activity of the enzyme was followed by a robust induction of the messenger RNA (mRNA) expression of the enzyme. The mechanism of arginase II activation involved the dissociation of the enzyme from the microtubule cytoskeleton. Accordingly, microtubule disruption by nocodazole increased arginase II activity under basal conditions, whereas stabilization of the microtubule with epothilone B prevented the oxLDL-induced activation of arginase. With these observations, the authors not only discovered a new road to endothelial dysfunction induced by oxLDL, they also identified a new mechanism of arginase activation.
The exact mechanism of interaction of arginase with the microtubule however requires further research. From the study of Ryoo et al it appears that primarily the degree of tubulin polymerization determines the interaction of arginase with the microtubule network. Nevertheless, the interacting domains have not yet been identified and it cannot be excluded that adapter proteins, which might also be involved in signal transduction are required in the process.
It is currently unknown how oxLDL destabilizes the microtubule and thus facilitates the release of arginase from these filaments. Small GTPases of the Rho family positively as well as negatively affect microtubule stability.20 It has recently been noted that also thrombin increases the arginase II activity in human umbilical vein endothelial cells via a nontranscriptional mechanism.21 Intriguingly, in that study it was observed that arginase II activation could be prevented by the inhibition of RhoA and RhoA-dependent kinase (ROCK). Whether thrombin-induced activation of arginase II involved dissociation from microtubule, however, was not studied.
It is remarkable that once again Rho family proteins appear to be the "bad guy" for endothelial function. Indeed, RhoA is activated by oxLDL.22 It has previously been reported that RhoA is involved in destabilizing eNOS mRNA23 and another member of the Rho family, Rac, is required for NADPH oxidase activation and thus initiation of oxidative stress.24 The signaling of Rho GTPases requires the interaction of the proteins with the cell membrane via a geranyl-geranyl anchor. One of the pleiotropic effects of the lipid-lowering HMG-CoA reductase inhibitors (statins) is the prevention of this lipid anchoring of Rho GTPases.25 It might be speculated that inhibition of arginase II is another pleiotropic effect of statins, but this hypothesis needs to be tested.
In the present study Ryoo et al used oxLDL which was generated by copper oxidation. Although this is certainly the standard procedure to obtain oxLDL, the method has be criticized as trace amounts of copper may have serious effects on cells and as the degree of oxidation often exceeds that observed in vivo. Moreover, oxidative modification of LDL is only one way to render it proatherogenic. Consequently, the data obtained by Ryoo et al require confirmation to some extent. It would be helpful to demonstrate that the effects do not occur with LDL and that the signaling involves LOX-1. Moreover, it would be important to study arginase II activity in hyperlipidemic animals. Ryoo et al already made a first step in this direction by using ex vivo incubation of aortic rings with oxLDL. Moreover, it has been observed previously that arginase activity is increased in aortas of ApoE–/– mice.21 The hyperlipidemia in this transgenic strain, however, is because of the accumulation of very low density lipoprotein (VLDL) and not LDL. Atherosclerotic tissue also comprises several different cell types with arginase activity such as macrophages and smooth muscle cells and thus it will be difficult to identify endothelium-selective effects in animal models. Further work will be needed to demonstrate that the mechanism proposed by Ryoo et al contributes to LDL-induced endothelial dysfunction in vivo.
 |
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
2. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc Res. 2006; 69: 36–45.
3. Bickel PE, Freeman MW. Rabbit aortic smooth muscle cells express inducible macrophage scavenger receptor messenger RNA that is absent from endothelial cells. J Clin Invest. 1992; 90: 1450–1457.[Medline] [Order article via Infotrieve]
4. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997; 386: 73–77.[CrossRef][Medline] [Order article via Infotrieve]
5. Mehta JL, Chen J, Yu F, Li DY. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res. 2004; 64: 243–249.
6. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N, Mehta JL. Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res. 2003; 57: 238–243.
7. Ohgushi M, Kugiyama K, Fukunaga K, Murohara T, Sugiyama S, Miyamoto E, Yasue H. Protein kinase C inhibitors prevent impairment of endothelium-dependent relaxation by oxidatively modified LDL. Arterioscler Thromb Vasc Biol. 1993; 13: 1525–1532.
8. Sugiyama S, Kugiayama K, Ohgushi M, Hujimoto K, Yasue H. Lysophosphatidylcholin in oxidized low-density lipoprotein increases endothelial susceptibility to polymorphonuclear leukocyte-induced endothelial dysfunction in procine coronary arteries: Role of protein kinase C. Circ Res. 1994; 74: 565–575.
9. Nihei S, Yamashita K, Tasaki H, Ozumi K, Nakashima Y. Oxidized low-density lipoprotein-induced apoptosis is attenuated by insulin-activated phosphatidylinositol 3-kinase/Akt through p38 mitogen-activated protein kinase. Clin Exp Pharmacol Physiol. 2005; 32: 224–229.[CrossRef][Medline] [Order article via Infotrieve]
10. Everson WV, Smart EJ. Influence of caveolin, cholesterol, and lipoproteins on nitric oxide synthase: implications for vascular disease. Trends Cardiovasc Med. 2001; 11: 246–250.[CrossRef][Medline] [Order article via Infotrieve]
11. Fleming I, Mohamed A, Galle J, Turchanowa L, Brandes RP, Fisslthaler B, Busse R. Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha. Cardiovasc Res. 2005; 65: 897–906.
12. Girerd XJ, Hirsch AT, Cooke JP, Dzau VJ, Creager MA. L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits. Circ Res. 1990; 67: 1301–1308.
13. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991; 338: 1546–1550.[CrossRef][Medline] [Order article via Infotrieve]
14. Böger RH, Bode-Böger SM, Brandes RP, Phivthong-ngam L, Böhme M, Nafe R, Mügge A, Frölich JC. Dietary L-arginine reduces the progression, but does not induce regression of atherosclerosis in cholesterol-fed rabbits - comparison with lovastatin. Circulation. 1997; 96: 1282–1290.
15. Brandes RP, Brandes S, Boger RH, Bode-Boger SM, Mugge A. L-arginine supplementation in hypercholesterolemic rabbits normalizes leukocyte adhesion to non-endothelial matrix. Life Sci. 2000; 66: 1519–1524.[CrossRef][Medline] [Order article via Infotrieve]
16. Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res. 2000; 87: 99–105.
17. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.
18. Ryoo S, Lemmon C, Soucy K, Gupta G, White A, Nyhan D, Shoukas A, Romer L, Berkowitz D OxLDL-dependent endothelial arginase II activation contributes to imaired NO signaling. Circ Res. 2006; 99: 951–960.
19. Morris SM, Jr. Arginine metabolism in vascular biology and disease. Vasc Med. 2005; 10 Suppl 1: S83–S87.
20. Gundersen GG, Cook TA. Microtubules and signal transduction. Curr Opin Cell Biol. 1999; 11: 81–94.[CrossRef][Medline] [Order article via Infotrieve]
21. Ming XF, Barandier C, Viswambharan H, Kwak BR, Mach F, Mazzolai L, Hayoz D, Ruffieux J, Rusconi S, Montani JP, Yang Z. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation. 2004; 110: 3708–3714.
22. Galle J, Mameghani A, Bolz SS, Gambaryan S, Gorg M, Quaschning T, Raff U, Barth H, Seibold S, Wanner C, Pohl U. Oxidized LDL and its compound lysophosphatidylcholine potentiate AngII-induced vasoconstriction by stimulation of RhoA. J Am Soc Nephrol. 2003; 14: 1471–1479.
23. Laufs U, LaFata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97: 1129–1135.
24. Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000; 20: 61–69.
25. Laufs U, Liao JK. Targeting Rho in cardiovascular disease. Circ Res. 2000; 87: 526–528.
Related Article:
Circ. Res. 2006 99: 951-960.
This article has been cited by other articles:
 |
|
 |
|
  S. Sankaralingam, H. Xu, and S. T. Davidge Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia Cardiovasc Res, September 3, 2009; (2009) cvp277v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Vanhoutte Arginine and Arginase: Endothelial NO Synthase Double Crossed? Circ. Res., April 25, 2008; 102(8): 866 - 868. [Full Text] [PDF]
|
|
|
|
|
|
S. Ryoo, G. Gupta, A. Benjo, H. K. Lim, A. Camara, G. Sikka, H. K. Lim, J. Sohi, L. Santhanam, K. Soucy, et al. Endothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis Circ. Res., April 25, 2008; 102(8): 923 - 932. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||