Skip to main content

Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis

Current Diabetes Reports volume 5, pages 17–23 (2005)Cite this article

Abstract

There is a complex pathophysiologic scenario involving nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the reduction in bioactivity of eNOS with subsequent impaired release of NO. An important mechanism is local enhanced degradation of NO by increased generation of reactive oxygen species and other free radicals, with subsequent cascade of oxidationsensitive mechanisms in the arterial wall. Novel molecular approaches have resulted in the development of new strains of mice lacking eNOS. These experimental models will help to understand how to implement NO-based therapies against atherosclerosis. L-arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. The target or goal for new drugs should be the complete restoration of NOmediated signaling pathways in atherosclerotic arteries.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

References and Recommended Reading

  1. Ignarro LJ, Cirino G, Casini A, Napoli C: Nitric oxide as a signaling molecule in the vascular system: an overview. J Cardiovasc Pharmacol 1999, 34:876–884.

    Article  Google Scholar 

  2. Napoli C, Ignarro LJ: Nitric oxide and atherosclerosis. Nitric Oxide 2001, 5:88–97.

    PubMed  Article  CAS  Google Scholar 

  3. Napoli C: Nitric oxide and atherosclerotic lesion progression: an overview. J Card Surg 2002, 17:355–362.

    PubMed  Article  Google Scholar 

  4. Furchgott RF: Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep 1999, 19:235–251.

    PubMed  Article  CAS  Google Scholar 

  5. Ignarro LJ, Napoli C, Loscalzo J: Nitric oxide-donating compounds and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res 2002, 90:21–28.

    PubMed  Article  CAS  Google Scholar 

  6. Napoli C, Ignarro LJ: Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 2003, 43:97–123. This exaustive review reports the state of the art of drugs based on interaction with NO.

    PubMed  Article  CAS  Google Scholar 

  7. Napoli C, Lerman LO: Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia. Mayo Clin Proc 2001, 76:619–631.

    PubMed  CAS  Article  Google Scholar 

  8. de Nigriws F, Lerman A, Ignarro LJ, et al.: Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol Med 2003, 9:351–359. This review reports the novel interactions among oxidation-sensitive mechanisms, NO, and vascular damage.

    Article  CAS  Google Scholar 

  9. Drexler H: Nitric oxide and coronary endothelial dysfunction in humans. Cardiovasc Res 1999, 43:572–579.

    PubMed  Article  CAS  Google Scholar 

  10. Rodriguez-Porcel M, Lerman LO, Herrmann J, et al.: Hypercholesterolemia and hypertension have synergistic deleterious effects on coronary endothelial function. Arterioscler Thromb Vasc Biol 2003, 23:885–891. This is the first convincing demonstration that hypercholesterolemia and hypertension have synergistic deleterious effects on coronary endothelial function.

    PubMed  Article  CAS  Google Scholar 

  11. Verbeuren TJ, Coene MC, Jordaens FH, et al.: Effect of hypercholesterolemia on vascular reactivity in the rabbit: II. Influence of treatment with dipyridamole on endotheliumdependent and endothelium-independent responses in isolated aortas of control and hypercholesterolemic rabbits. Circ Res 1986, 59:496–504.

    PubMed  CAS  Google Scholar 

  12. Meredith IT, Anderson TJ, Uehata A, et al.: Role of endothelium in ischemic coronary syndromes. Am J Cardiol 1993, 72:27C-31C.

    PubMed  Article  CAS  Google Scholar 

  13. Cooke JP: Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000, 20:2032–2037.

    PubMed  CAS  Google Scholar 

  14. Boger RH, Bode-Boger SM, Szuba A, et al.: Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998, 98:1842–1847.

    PubMed  CAS  Google Scholar 

  15. Wever RM, Luscher TF, Rabelink TJ: Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 1998, 97:108–112.

    PubMed  CAS  Google Scholar 

  16. Cardillo C, Kilcoyne CM, Cannon RO III, et al.: Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 1997, 30:57–63.

    PubMed  CAS  Google Scholar 

  17. Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000, 87:840–844.

    PubMed  CAS  Google Scholar 

  18. Tousoulis D, Tentolouris C, Crake T, et al.: Basal and flowmediated NO production by atheromatous coronary arteries. J Am Coll Cardiol 1997, 29:1256–1262.

    PubMed  Article  CAS  Google Scholar 

  19. Creager MA, Galagher 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 

  20. Drexler H, Zeiher A, Meinzer K, Just H: Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet 1991, 33:1546–1550.

    Article  Google Scholar 

  21. Tousoulis D, Davies G, Tentolouris C, et al.: Coronary stenosis dilation induced by L-arginine. Lancet 1997, 349:1812–1813.

    PubMed  Article  CAS  Google Scholar 

  22. Lerman A, Burnett JC Jr, Higano ST, et al.: Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998, 97:2123–2128.

    PubMed  CAS  Google Scholar 

  23. Cooke JP, Oka RK: Atherogenesis and the arginine hypothesis. Curr Atheroscler Rep 2001, 3:252–259.

    PubMed  CAS  Google Scholar 

  24. Tousoulis D, Davies GJ, Tentolouris C, et al.: Effects of changing the availability of the substrate for NO synthase by L-arginine administration on coronary vasomotor tone in angina patients with angiographically narrowed and in patients with normal coronary arteries. Am J Cardiol 1998, 82:1110–1113.

    PubMed  Article  CAS  Google Scholar 

  25. Blum A, Porat R, Rosenschein U, et al.: Clinical and inflammatory effects of dietary L-arginine in patients with intractable angina pectoris. Am J Cardiol 1999, 83:1488–1490.

    PubMed  Article  CAS  Google Scholar 

  26. Fujita H, Yamabe H, Yokoyama M: Effect of L-arginine administration on myocardial thallium-201 perfusion during exercise in patients with angina pectoris and normal coronary angiograms. J Nucl Cardiol 2000, 7:97–102.

    PubMed  Article  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. Tousoulis D, Davies GJ, Tentolouris C, et al.: Vasomotor effects of L- and D-arginine in stenotic atheromatous coronary plaque. Heart 2001, 86:296–301.

    PubMed  Article  CAS  Google Scholar 

  29. de Nigris F, Lerman LO, Ignarro-Williams S, et al.: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial nitric oxide synthase activity at sites of disturbed shear stress. Proc Natl Acad Sci U S A 2003, 100:1420–1425. This is the first evidence that L-arginine may modulate gene expression at the site of shear stress and atherosclerosis.

    PubMed  Article  CAS  Google Scholar 

  30. Luoma JS, Yla-Herttuala S: Expression of inducible NO synthase in macrophages and smooth muscle cells in various types of human atherosclerotic lesions. Virchows Arch 1999, 434:561–568.

    PubMed  Article  CAS  Google Scholar 

  31. Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med 1999, 340:115–126.

    PubMed  Article  CAS  Google Scholar 

  32. Baker CS, Hall RJ, Evans TJ, et al.: Cyclooxygenase-2 is widely expressed in atherosclerotic lesion affecting native and transplanted human coronary arteries and colocalizes with inducible NO synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol 1999, 19:646–655.

    PubMed  CAS  Google Scholar 

  33. Mallat Z, Heymes C, Ohan J, et al.: Expression of interleukin- 10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol 1999, 19:61–66.

    Google Scholar 

  34. Hingorani AD, Liang CF, Fatibene J, et al.: A common variant of the endothelial NO synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999, 100:1515–1520.

    PubMed  CAS  Google Scholar 

  35. Guzik TJ, Black E, West NE, et al.: Relationship between the G894T polymorphism (Glu298Asp variant) in endothelial NO synthase and NO-mediated endothelial function in human atherosclerosis. Am J Med Genet 2001, 100:130–137.

    PubMed  Article  CAS  Google Scholar 

  36. Fowkes FG, Lee AJ, Hau CM, et al.: Methylene tetrahydrofolate reductase (MTHFR) and NO synthase ( e NOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh Artery Study. Atherosclerosis 2000, 150:179–185.

    PubMed  Article  CAS  Google Scholar 

  37. Mozes G, Kullo IJ, Mohacsi TG, et al.: Ex vivo gene transfer of endothelial NO synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine. Atherosclerosis 1998, 141:265–271.

    PubMed  Article  CAS  Google Scholar 

  38. Behr D, Rupin A, Fabiani JN, Verbeuren TJ: Distribution and prevalence of inducible NO synthase in atherosclerotic vessels of long-term cholesterol-fed rabbit. Atherosclerosis 1999, 142:335–344.

    PubMed  Article  CAS  Google Scholar 

  39. Qian H, Neplioueva V, Shetty GA, et al.: NO synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 1999, 99:2979–2982.

    PubMed  CAS  Google Scholar 

  40. Wang BY, Ho PS, Schwarzacher SP, et al.: Regression of atherosclerosis: role of NO and apoptosis. Circulation 1999, 99:1236–1241.

    PubMed  CAS  Google Scholar 

  41. Kauser K, da Cunha V, Fitch R, et al.: Role of endogenous NO in progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Physiol 2000, 278:H1679-H1685.

    CAS  Google Scholar 

  42. Egashira K, Koyanagi M, Kitamoto S, et al.: Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis. FASEB J 2000, 14:1974–1978.

    PubMed  Article  CAS  Google Scholar 

  43. Kuhlencordt PJ, Gyurko R, Han F, et al.: Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial NO synthase double-knockout mice. Circulation 2001, 104:448–454.

    PubMed  CAS  Google Scholar 

  44. Calara F, Silvestre M, Casanada F, et al.: Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 2001, 195:257–263. First systematic study that shows the occurrence of spontaneous atherosclerotic plaque rupture in hypercholesterolemic mice.

    PubMed  Article  CAS  Google Scholar 

  45. Chen J, Kuhlencordt PJ, Astern J, et al.: Hypertension does not account for the accelerated atherosclerosis and development of aneurysms in male apolipoprotein e/endothelial NO synthase double knockout mice. Circulation 2001, 104:2391–2394.

    PubMed  CAS  Google Scholar 

  46. Lee PC, Wang ZL, Qian S, et al.: Endothelial NO synthase protects aortic allografts from the development of transplant arteriosclerosis. Transplantation 2000, 69:1186–1192.

    PubMed  Article  CAS  Google Scholar 

  47. Shi W, Wang X, Shih DM, et al.: Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase. Circulation 2002, 105:2078–2082.

    PubMed  Article  CAS  Google Scholar 

  48. Lamping K, Faraci F: Enhanced vasoconstrictor responses in eNOS deficient mice. Nitric Oxide 2003, 8:207–213.

    PubMed  Article  CAS  Google Scholar 

  49. Napoli C, Lerman LO, Sica V, et al.: Microarray analysis: a novel research tool for cardiovascular scientists and physicians. Heart 2003, 89:597–604.

    PubMed  Article  CAS  Google Scholar 

  50. Napoli C, de Nigris F, Palinski W: Multiple role of reactive oxygen species in the arterial wall. J Cell Biochem 2001, 82:674–682.

    PubMed  Article  CAS  Google Scholar 

  51. Witztum JL: The oxidation hypothesis of atherosclerosis. Lancet 1994, 344:793–795.

    PubMed  Article  CAS  Google Scholar 

  52. Napoli C, D’Armiento FP, Witztum JL, et al.: Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997, 100:2680–2690.

    PubMed  CAS  Google Scholar 

  53. Napoli C, Glass CK, Witztum JL, et al.: Influence of maternal hypercholesterolemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999, 354:1234–1241.

    PubMed  Article  CAS  Google Scholar 

  54. Flavahan NA: Atherosclerosis or lipoprotein-induced endothelial dysfunction. Circulation 1992, 85:1927–1938.

    PubMed  CAS  Google Scholar 

  55. Chin JH, Azhar S, Hoffman BB: Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest 1992, 89:10–18.

    PubMed  CAS  Article  Google Scholar 

  56. Pritchard KA Jr, Groszek L, Sessa WC, et al.: Native low-density lipoprotein increases endothelial cell NO synthase generation of superoxide anion. Circ Res 1995, 77:510–518.

    PubMed  CAS  Google Scholar 

  57. Vergnani L, Hatrik S, Ricci F, et al.: Effect of native and oxidized low-density lipoprotein on endothelial NO and superoxide production: key role of L-arginine availability. Circulation 2000, 101:1261–1266.

    PubMed  CAS  Google Scholar 

  58. Napoli C, Paternò R, Faraci FM, et al.: Mildly oxidized low-density lipoprotein impairs responses of carotid but not basilar artery in rabbits. Stroke 1997, 28:2266–2272.

    PubMed  CAS  Google Scholar 

  59. Napoli C, Witztum JL, de Nigris F, et al.: Intracranial arteries of human fetuses are more resistant to hypercholesterolemiainduced fatty streak formation than extracranial arteries. Circulation 1999, 99:2003–2010.

    PubMed  CAS  Google Scholar 

  60. D’Armiento FP, Bianchi A, de Nigris F, et al.: Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classical risk factors for atherosclerosis. Stroke 2001, 32:2472–2480.

    PubMed  CAS  Google Scholar 

  61. Napoli C, Lerman LO, de Nigris F, et al.: Glycoxidized low-density lipoprotein downregulates endothelial nitric oxide synthase in human coronary cells. J Am Coll Cardiol 2002, 40:1515–1522.

    PubMed  Article  CAS  Google Scholar 

  62. Napoli C, Ackah E, De Nigris F, et al.: Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice. Proc Natl Acad Sci U S A 2002, 99:12467–12470.

    PubMed  Article  CAS  Google Scholar 

  63. Frei B: On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction. Proc Soc Exp Biol Med 1999, 222:196–204.

    PubMed  Article  CAS  Google Scholar 

  64. Palinski W, Napoli C: The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. FASEB J 2002, 16:1348–1360.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 23-305 Center for Health Sciences, 90095, Los Angeles, CA, USA

    Louis J. Ignarro PhD & Claudio Napoli MD, PhD

Authors
  1. Louis J. Ignarro PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Napoli MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ignarro, L.J., Napoli, C. Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis. Curr Diab Rep 5, 17–23 (2005). https://doi.org/10.1007/s11892-005-0062-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-005-0062-8

Keywords

  • Nitric Oxide
  • Arginase
  • Coronary Endothelial Function
  • Fatty Streak Formation
  • Edinburgh Artery Study