Skip to main content

Advertisement

SpringerLink
Log in

Endothelial arginase: A new target in atherosclerosis

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Decreased endothelial nitric oxide (NO) bioavailability as it relates to endothelial dysfunction plays an important role in various cardiovascular disorders, including atherosclerosis. Recent research has provided evidence that endothelial dysfunction in atherosclerosis is not primarily caused by decreased endothelial NO synthase (eNOS) gene expression, but rather deregulation of eNOS enzymatic activity, which contributes to the increased oxidative stress in atherosclerosis. Among other mechanisms, the substrate L-arginine is an important limiting factor for NO production. Emerging evidence demonstrates that L-arginine is not only converted to NO via eNOS, but also metabolized to urea and L-ornithine via arginase in endothelial cells. Hence, arginase competes with eNOS for the substrate L-arginine, resulting in deceased NO production. There are an increasing number of studies showing that enhanced arginase gene expression and/or activity contribute to endothelial dysfunction in various cardiovascular disorders, including atherosclerosis. Thus, endothelial arginase may represent a new therapeutic target in atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Libby P, Theroux P: Pathophysiology of coronary artery disease. Circulation 2005, 111:3481–3488.

    Article  PubMed  Google Scholar 

  2. Halcox JP, Schenke WH, Zalos G, et al.: Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002, 106:653–658.

    Article  PubMed  Google Scholar 

  3. Bugiardini R, Manfrini O, Pizzi C, et al.: Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation 2004, 109:2518–2523.

    Article  PubMed  Google Scholar 

  4. Yang Z, Luscher TF: Vascular endothelium. In PanVascularMedicine. Edited by Lanzer P, Topol EJ. Berlin-Heidelberg-New York: Springer; 2002:190–204.

    Google Scholar 

  5. Knowles JW, Reddick RL, Jennette JC, et al.: Enhanced atherosclerosis and kidney dysfunction in eNOS (-/-)Apoe(-/-) mice are ameliorated by enalapril treatment. J Clin Invest 2000, 105:451–458.

    PubMed  CAS  Google Scholar 

  6. Kauser K, da Cunha V, Fitch R, et al.: Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Physiol Heart Circ Physiol 2000, 278:H1679-H1685.

    PubMed  CAS  Google Scholar 

  7. Sessa WC: eNOS at a glance. J Cell Sci 2004, 117:2427–2429.

    Article  PubMed  CAS  Google Scholar 

  8. Oemar BS, Tschudi MR, Godoy N, et al.: Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 1998, 97:2494–2498.

    PubMed  CAS  Google Scholar 

  9. Davignon J, Ganz P: Role of endothelial dysfunctionin atherosclerosis. Circulation 2004, 109(23 Suppl 1): III27-III32.

    PubMed  Google Scholar 

  10. Matsumoto T, d’Uscio LV, Eguchi D, et al.: Protective effect of chronic vitamin C treatment on endothelial function of apolipoprotein E-deficient mouse carotid artery. J Pharmacol Exp Ther 2003, 306:103–108.

    Article  PubMed  CAS  Google Scholar 

  11. Godecke A, Ziegler M, Ding Z, et al.: Endothelial dysfunction of coronary resistance vessels in apoE-/-mice involves NO but not prostacyclin-dependent mechanisms. Cardiovasc Res 2002, 53:253–262.

    Article  PubMed  CAS  Google Scholar 

  12. d’Uscio LV, Baker TA, Mantilla CB, et al.: Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2001, 21:1017–1022.

    PubMed  CAS  Google Scholar 

  13. Ming XF, Barandier C, Viswambharan H, et al.: Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 2004, 110:3708–3714. This is the first study showing that endothelial arginase activity is regulated by the Rho/ROCK pathway. Arginase activity is increased in atherosclerotic aortas in ApoE-/-mice and plays a substantial role in endothelial dysfunction in atherosclerosis.

    Article  PubMed  CAS  Google Scholar 

  14. Wilcox JN, Subramanian RR, Sundell CL, et al.: Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997, 17:2479–2488.

    PubMed  CAS  Google Scholar 

  15. Fukuchi M, Giaid A: Endothelial expression of endothelial nitric oxide synthase and endothelin-1 in human coronary artery disease. Specific reference to underlying lesion. Lab Invest 1999, 79:659–670.

    PubMed  CAS  Google Scholar 

  16. Rossi ML, Marziliano N, Merlini PA, et al.: Phenotype commitment in vascular smooth muscle cells derived from coronary atherosclerotic plaques: differential gene expression of endothelial nitric oxide synthase. Eur J Histochem 2005, 49:39–46.

    PubMed  CAS  Google Scholar 

  17. Ozaki M, Kawashima S, Yamashita T, et al.: Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 2002, 110:331–340.

    Article  PubMed  CAS  Google Scholar 

  18. van HaperenR, de WaardM, van DeelE, et al.: Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide. J Biol Chem 2002, 277:48803–48807.

    Article  PubMed  Google Scholar 

  19. Munzel T, Daiber A, Ullrich V, et al.: Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 2005, 25:1551–1557.

    Article  PubMed  CAS  Google Scholar 

  20. Drexler H, Zeiher AM, Meinzer K, et al.: Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991, 338:1546–1550.

    Article  PubMed  CAS  Google Scholar 

  21. Cooke JP, Singer AH, Tsao P, et al.: Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992, 90:1168–1172.

    Article  PubMed  CAS  Google Scholar 

  22. Creager MA, Gallagher SJ, Girerd XJ, et al.: L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992, 90:1248–1253.

    PubMed  CAS  Google Scholar 

  23. Dubois-Rande JL, Zelinsky R, Roudot F, et al.: Effects of infusion of L-arginine into the left anterior descending coronary artery on acetylcholine-induced vasoconstriction of human atheromatous coronary arteries. Am J Cardiol 1992, 70:1269–1275.

    Article  PubMed  CAS  Google Scholar 

  24. Loscalzo J: Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol 2003, 23:3–5. A critical editorial comment analyzing controversial results with L-arginine supplemental therapy obtained from experimental and clinical studies.

    Article  PubMed  CAS  Google Scholar 

  25. Jeremy RW, McCarron H, Sullivan D: Effects of dietary L-arginine on atherosclerosis and endothelium-dependent vasodilatation in the hypercholesterolemic rabbit. Response according to treatment duration, anatomic site, and sex. Circulation 1996, 94:498–506.

    PubMed  CAS  Google Scholar 

  26. Oomen CM, van Erk MJ, Feskens EJ, et al.: Arginine intake and risk of coronary heart disease mortality in elderly men. Arterioscler Thromb Vasc Biol 2000, 20:2134–2139.

    PubMed  CAS  Google Scholar 

  27. Blum A, Hathaway L, Mincemoyer R, et al.: Oral L-arginine in patients with coronary artery disease on medical management. Circulation 2000, 101:2160–2164.

    PubMed  CAS  Google Scholar 

  28. Walker HA, McGing E, Fisher I, et al.: Endotheliumdependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance. J Am Coll Cardiol 2001, 38:499–505.

    Article  PubMed  CAS  Google Scholar 

  29. Wennmalm A, Edlund A, Granstrom EF, et al.: Acute supplementation with the nitric oxide precursor L-arginine does not improve cardiovascular performance in patients with hypercholesterolemia. Atherosclerosis 1995, 118:223–231.

    Article  PubMed  CAS  Google Scholar 

  30. Miller HI, Dascalu A, Rassin TA, et al.: Effects of an acute dose of L-arginine during coronary angiography in patients with chronic renal failure: a randomized, parallel, double-blind clinical trial. Am J Nephrol 2003, 23:91–95.

    Article  PubMed  CAS  Google Scholar 

  31. Chen J, Kuhlencordt P, Urano F, et al.: Effects of chronic treatment with L-arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase doubleknockout mice. Arterioscler Thromb Vasc Biol 2003, 23:97–103.

    Article  PubMed  CAS  Google Scholar 

  32. Simonet S, Rupin A, Badier-Commander C, et al.: Evidence for superoxide anion generation in aortas of cholesterolfed rabbits treated with L-arginine. Eur J Pharmacol 2004, 492:211–216.

    Article  PubMed  CAS  Google Scholar 

  33. Wu G, Morris SMJr: Arginine metabolism: nitric oxide and beyond. Biochem J 1998, 336:1–17.

    PubMed  CAS  Google Scholar 

  34. Durante W, Liao L, Reyna SV, et al.: Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: role in polyamine and collagen synthesis. Circulation 2001, 103:1121–1127.

    PubMed  CAS  Google Scholar 

  35. Morris SMJr, Bhamidipati D, Kepka-Lenhart D: Human type II arginase: sequence analysis and tissue-specific expression. Gene 1997, 193:157–161.

    Article  PubMed  CAS  Google Scholar 

  36. Cederbaum SD, Yu H, Grody WW, et al.: Arginases I and II: Do their functions overlap? Mol Genet Metab 2004, 81(Suppl 1):S38-S44.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang C, Hein TW, Wang W, et al.: Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 2001, 15:1264–1266.

    Article  PubMed  CAS  Google Scholar 

  38. Buga GM, Singh R, Pervin S, et al.: Arginase activity in endothelial cells: inhibition by NG-hydroxy-L-arginine during high-output NO production. Am J Physiol 1996, 271:H1988-H1998.

    PubMed  CAS  Google Scholar 

  39. Bachetti T, Comini L, Francolini G, et al.: Arginase pathway in human endothelial cells in pathophysiological conditions. J Mol Cell Cardiol 2004, 37:515–523.

    Article  PubMed  CAS  Google Scholar 

  40. Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, et al.: Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 2001, 283:923–927.

    Article  PubMed  CAS  Google Scholar 

  41. Cama E, Colleluori DM, Emig FA, et al.: Human arginase II: crystal structure and physiological role in male and female sexual arousal. Biochemistry 2003, 42:8445–8451.

    Article  PubMed  CAS  Google Scholar 

  42. Berkowitz DE, White R, Li D, et al.: Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003, 108:2000–2006.

    Article  PubMed  CAS  Google Scholar 

  43. Sakai Y, Masuda H, Kihara K, et al.: Involvement of increased arginase activity in impaired cavernous relaxation with aging in the rabbit. J Urol 2004, 172:369–373.

    Article  PubMed  CAS  Google Scholar 

  44. Hein TW, Zhang C, Wang W, et al.: Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J 2003, 17:2328–2330.

    PubMed  CAS  Google Scholar 

  45. Zhang C, Hein TW, Wang W, et al.: Upregulation of vascular arginase in hypertension decreases nitric oxidemediated dilation of coronary arterioles. Hypertension 2004, 44:935–943.

    Article  PubMed  CAS  Google Scholar 

  46. Johnson FK, Johnson RA, Peyton KJ, et al.: Arginase inhibitionrestores arteriolar endothelial function in Dahl ratswith salt-induced hypertension. Am J Physiol Regul Integr Comp Physiol 2004, Dec 9, [Epub ahead of print].

  47. Demougeot C, Prigent-Tessier A, Marie C, et al.: Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens 2005, 23:971–978. An important study demonstrating that arginase expression and activity are increased in spontaneous hypertensive rats, and treatment of the rat with an arginase inhibitor improves endothelial function and decreases blood pressure in the animals.

    Article  PubMed  CAS  Google Scholar 

  48. Xu W, Kaneko FT, Zheng S, et al.: Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004, 18:1746–1748.

    PubMed  CAS  Google Scholar 

  49. Morris CR, Kato GJ, Poljakovic M, et al.: Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005, 294:81–90. The first clinical study showing that increased arginase activity in plasma and red blood cells is independently associated with pulmonary hypertension and mortality in patients with sickle cell disease.

    Article  PubMed  CAS  Google Scholar 

  50. Nelin LD, Chicoine LG, Reber KM, et al.: Cytokineinducedendothelial arginase expression is dependent onepidermal growth factor receptor. Am J Respir Cell Mol Biol 2005, Jun 30, [Epub ahead of print].

Download references

Author information

Authors and Affiliations

  1. Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700, Fribourg, Switzerland

    Zhihong Yang MD

Authors
  1. Zhihong Yang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiu-Fen Ming MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhihong Yang MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, Z., Ming, XF. Endothelial arginase: A new target in atherosclerosis. Current Science Inc 8, 54–59 (2006). https://doi.org/10.1007/s11906-006-0041-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-006-0041-8

Keywords

Search

Navigation