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Atherogenesis and the arginine hypothesis

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Abstract

In patients who have elevated levels of plasma ADMA, a relative deficiency of L-arginine has been found to contribute to the pathophysiology of athersclerosis, causing vasoconstriction, and accelerating atherogenesis. This finding—that there is a relative deficiency of L-arginine in atherosclerotic disease—is a breakthrough that will open new avenues of therapy.

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References and Recommended Reading

  1. Pohl U, et al.: Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 1986, 8:37–44.

    PubMed  CAS  Google Scholar 

  2. Cooke JP, et al.: Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 1991, 88:1663–1671.

    PubMed  CAS  Google Scholar 

  3. Rees D, Palmer R, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A 1989, 86:3375–3378.

    Article  PubMed  CAS  Google Scholar 

  4. Vallance P, Collier J, Moncada S: Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989, 2:997–1000.

    Article  PubMed  CAS  Google Scholar 

  5. Cooke J, Dzau V: Nitric oxide synthase: role in the genesis of vascular disease. Annual Rev Med 1997, 48:489–509.

    Article  CAS  Google Scholar 

  6. Huang PL, et al.: Hypertension in mice lacking the gene for endothelial nitric oxide synthase [see comments]. Nature 1995, 377:239–242.

    Article  PubMed  CAS  Google Scholar 

  7. Creager MA, et al.: Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990, 86:228–234.

    PubMed  CAS  Google Scholar 

  8. Celermajer DS, et al.: Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994, 24:1468–1474.

    Article  PubMed  CAS  Google Scholar 

  9. Ludmer PL, et al.: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986, 315:1046–1051.

    Article  PubMed  CAS  Google Scholar 

  10. Nabel E, Selwyn A, Ganz P: Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol 1990, 16:349–356.

    Article  PubMed  CAS  Google Scholar 

  11. Garg UC, Hassid A: Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest, 1989, 83:1774–1777.

    PubMed  CAS  Google Scholar 

  12. Numaguchim K, et al.: Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 1995, 26:957–962.

    Google Scholar 

  13. Weidinger F, et al.: Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery. Circulation 1990, 81:1667–1679.

    PubMed  CAS  Google Scholar 

  14. von der Leyen HE, et al.: Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A 1995, 92:1137–1141.

    Article  PubMed  Google Scholar 

  15. Le Tourneau T, et al.: Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling. J Am Coll Cardiol 1999, 33:876–882.

    Article  PubMed  Google Scholar 

  16. De Caterina R, et al.: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995, 96:60–68.

    PubMed  Google Scholar 

  17. Tsao P, Wang B, Buitrago R: Nitric oxide regulates monocyte chemotactic protein-1. Circulation 1997, 96:1168–1172.

    Google Scholar 

  18. Collins T, et al.: Transcriptional regulation of endothelial cell adhesion molecules: NF- kappa B and cytokine-inducible enhancers. FASEB J 1995, 9:899–909.

    PubMed  CAS  Google Scholar 

  19. Cohen RA: The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 1995, 38:105–128.

    Article  PubMed  CAS  Google Scholar 

  20. Cohen GA, et al.: Nitric oxide regulates endothelium-dependent vasodilator responses in rabbit hindquarters vascular bed in vivo. Am J Physiol, 1996, 271:H133–139.

    PubMed  CAS  Google Scholar 

  21. Stamler J, et al.: N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ Res 1989, 65:789–795.

    PubMed  CAS  Google Scholar 

  22. Tsao P, McEnvoy LM, Drexler H: Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994, 89:2176–2182.

    PubMed  CAS  Google Scholar 

  23. Tsao P, et al.: L-arginine attenuates platelet reactivity in hypercholesterolemic rabbits. Arterioscler Thromb 1994, 14:1529–1533.

    PubMed  CAS  Google Scholar 

  24. Cayatte AJ, et al.: Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb 1994, 14:753–759.

    PubMed  CAS  Google Scholar 

  25. Naruse M, et al.: Effects of two calcium channel blockers on messenger RNA expression of endothelin-1 and nitric oxide synthase in cardiovascular tissue of hypertensive rats. J Hypertens 1999, 17:53–60.

    Article  PubMed  CAS  Google Scholar 

  26. Zeiher AM: Endothelial vasodilator dysfunction: pathogenetic link to myocardial ischaemia or epiphenomenon? Lancet 1996, 348(suppl 1):10–12.

    Article  Google Scholar 

  27. Zeiher AM, et al.: Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 1995, 91:2345–2352.

    PubMed  CAS  Google Scholar 

  28. Suwaidi J, et al.: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000, 101:948–954.

    PubMed  CAS  Google Scholar 

  29. Lerman A, et al.: Chronic L-arginine supplement improves coronary endothelial function in humans. Circulation 1997, Submitted for review.

  30. Ohara Y, Petersen TE, Harrison DG: Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993, 91:2546–2551.

    PubMed  CAS  Google Scholar 

  31. Rubanyi GM, Vanhoutte PM: Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol (Heart Circ Physiol 19) 1986, 250:H822-H827.

    CAS  Google Scholar 

  32. Beckman J, Koppenol W: Nitric oxide, superoxide, and peroxynitrite: the good, the bad, ad the ugly. Am J Physiol 1996, 271:C1424-C1437.

    PubMed  CAS  Google Scholar 

  33. Mugge A, et al.: Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991, 69:1293–1300.

    PubMed  CAS  Google Scholar 

  34. Gokce N, et al.: Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1999, 99:3234–3240.

    PubMed  CAS  Google Scholar 

  35. Ramasamy S, et al.: Modulation of expression of endothelial nitric oxide synthase by nordihydroguaiaretic acid, a phenolic antioxidant in cultured endothelial cells. Mol Pharmacol, 1999, 56:116–123.

    PubMed  CAS  Google Scholar 

  36. Pou S, et al.: Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 1992, 267:24173–24176.

    PubMed  CAS  Google Scholar 

  37. Stroes E, et al.: Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest, 1997, 99:41–46.

    PubMed  CAS  Google Scholar 

  38. Xia Y, et al.: Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 1998, 273:25804–25808.

    Article  PubMed  CAS  Google Scholar 

  39. Kirkwood A, et al.: Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res 1995, 77:510–518.

    Google Scholar 

  40. Vasquez-Vivar J, et al.: Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 1998, 95:9220–9225.

    Article  PubMed  CAS  Google Scholar 

  41. Huang A, et al.: Ascorbic acid enhances endothelial nitric oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 2000.

  42. Oemar B, et al.: Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 1998, 97:2494–2498.

    PubMed  CAS  Google Scholar 

  43. Liao J, et al.: Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995, 270:319–324.

    Article  PubMed  CAS  Google Scholar 

  44. Hingorani A, et al.: A common variant of the endothelial nitric oxide synthse (Glu298-Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999, 100:1515–1520.

    PubMed  CAS  Google Scholar 

  45. Vallance P, et al.: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992, 339:572–575.

    Article  PubMed  CAS  Google Scholar 

  46. Fujiwara N, et al.: Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitric oxide synthesis by salt intake. Circulation 2000, 101:856–861.

    PubMed  CAS  Google Scholar 

  47. Böger R, et al.: Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998, 98:1842–1847.

    PubMed  Google Scholar 

  48. Fard A, et al.: Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Atheroscler Thromb Vasc Biol 2000, 9:2039–2044.

    Google Scholar 

  49. Hand MF, Haynes WG, Webb DJ: Hemodialysis and L-arginine, but not D-arginine, correct renal failure- associated endothelial dysfunction. Kidney Int 1998, 53:1068–1077.

    Article  PubMed  CAS  Google Scholar 

  50. Usui M, et al.: Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci 1998, 62:2425–2430.

    Article  PubMed  CAS  Google Scholar 

  51. Holden DP, et al.: Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998, 178:551–556.

    Article  PubMed  CAS  Google Scholar 

  52. Surdacki A, et al.: Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999, 33:652–658.

    Article  PubMed  CAS  Google Scholar 

  53. Yu XJ, Li YJ, and Xiong Y: Increase of an endogenous inhibitor of nitric oxide synthesis in serum of high cholesterol fed rabbits. Life Sci 1994, 54:753–758.

    Article  PubMed  CAS  Google Scholar 

  54. Bode-Boger S, et al.: Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Comm, 1996, 219:598–603.

    Article  PubMed  CAS  Google Scholar 

  55. Matsuoka H, et al.: Asymetrical dimethlarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension 1997, 29:242–247.

    PubMed  CAS  Google Scholar 

  56. Boger RH, et al.: Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci 2001, 100:161–167.

    Article  PubMed  CAS  Google Scholar 

  57. Rickenbacher PR, et al.: Incidence and severity of transplant coronary artery disease early and up to 15 years after transplantation as detected by intravascular ultrasound [see comments]. J Am Coll Cardiol 1995, 25:171–177.

    Article  PubMed  CAS  Google Scholar 

  58. Scuteri A, et al.: Asymmetric dimethylarginine plasma concentrations correlate with blood pressure response to salt loading in normotensive postmenopausal women. Circulation 2000, 102(suppl):II-517.

    Google Scholar 

  59. Asagami T, et al.: Metformin attenuates plasma asymmetric dimethylarginine and monocyte adhesion in type 2 diabetes. Circulation 2000, 102:II-232.

    Google Scholar 

  60. Stuehlinger M, et al.: Homocysteine induced accumulation of asymmetric dimethylarginine—role of DDAH and effect of antioxidants. Circulation 2000, 102:II-177.

    Google Scholar 

  61. Najbauer J, et al.: Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J Biol Chem 1993, 268:10501–10509.

    PubMed  CAS  Google Scholar 

  62. Ghosh SK, Paik WK, Kim S: Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein- and histone-specific enzyme [published erratum appears in J Biol Chem 1989, Mar 25; 264:5313]. J Biol Chem 1988, 263:19024–19033.

    PubMed  CAS  Google Scholar 

  63. Tang J, Kao PN, Herschman HR: Protein arginine methyltransferase I (PRMT1), the predominant protein arginine methyltransferase in cells, interacts with and is regulated by interleukin enhancer binding factor 3. J Biol Chem 2000, 275:19866–19876.

    Article  PubMed  CAS  Google Scholar 

  64. Kakimoto Y, Akazawa S: Isolation and identification of NGNG- and NG, NG-Dimethyl-arginine, N-Mono-, Di-, and trimethyllysine, and glucosylgalactosul- and galactosyl-s-hydroxylsine from human urine. J Biol Chem 1970, 245:5751–5758.

    PubMed  CAS  Google Scholar 

  65. Ogawa T, Kimoto M, Sasaoka K: Occurrence of a new enzyme catalyzing the direct conversion of NG,NG- dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Comm 1987, 148:671–677.

    Article  PubMed  CAS  Google Scholar 

  66. Leiper JM, et al.: Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999, 343:209–214.

    Article  PubMed  CAS  Google Scholar 

  67. McDermott JR: Studies on the catabolism of Ng-methyl-arginine, Ng, Ng-dimethylarginine and Ng, Ng-dimethylarginine in the rabbit. Biochem J 1976, 154:179–184.

    PubMed  CAS  Google Scholar 

  68. MacAllister RJ, et al.: Concentration of dimethyl-L-arginine in the plasma of patients with end- stage renal failure. Nephrol Dial Transplant 1996, 11:2449–2452.

    PubMed  CAS  Google Scholar 

  69. MacAllister RJ, et al.: Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 1996, 119:1533–1540.

    PubMed  CAS  Google Scholar 

  70. Ito A, et al.: Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999, 99:3092–3095.

    PubMed  CAS  Google Scholar 

  71. Pollock JS, et al.: Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A 1991, 88:10480–10484.

    Article  PubMed  CAS  Google Scholar 

  72. Cooke J, et al.: Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991, 83:1057–1062.

    PubMed  CAS  Google Scholar 

  73. Drexler H, et al.: Correction of endothelial dysfunction in coronary microcirculation of hypercholeserolemic patients by L-arginine. Lancet 1991, 338:1546–1550.

    Article  PubMed  CAS  Google Scholar 

  74. Clarkson P, et al.: Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996, 97:1989–1994.

    Article  PubMed  CAS  Google Scholar 

  75. Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K: Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol 1997, 80:331–333.

    Article  PubMed  CAS  Google Scholar 

  76. Boger R, Bode-Boger S, Thiele W: Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998, 32:1336–1344.

    Article  PubMed  CAS  Google Scholar 

  77. Lerman A, et al.: Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans [see comments]. Circulation 1998, 97:2123–2128.

    PubMed  CAS  Google Scholar 

  78. McDonald KK, et al.: A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the “arginine paradox”. J Biol Chem 1997, 272:31213–31216.

    Article  PubMed  CAS  Google Scholar 

  79. Wei LH, et al.: IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells. Am J Physiol Cell Physiol 2000, 279:C248–256.

    PubMed  CAS  Google Scholar 

  80. Faraci FM, Brian Jr. JE, Heistad DD: Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995, 269:H1522–1527.

    PubMed  CAS  Google Scholar 

  81. Maxwell A, et al.: Limb blood flow during exercise is dependent upon nitric oxide. Circulation 1998, 84:369–374.

    Google Scholar 

  82. Chan JR, et al.: Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Throb Vasc Biol, 2000.

  83. Theilmeier G, et al.: Adhesiveness of mononuclear cells in hypercholesterolemic humans is normalized by dietary L-arginine. Arterioscler Thromb Vasc Biol 1997, 17:3557–3564.

    PubMed  CAS  Google Scholar 

  84. Adams MR, et al.: Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion t o endothelial cells in young men with coronary artery disease. Atherosclerosis 1997, 129:261–269.

    Article  PubMed  CAS  Google Scholar 

  85. Maxwell AJ, Anderson BA, Cooke JP: Nutritional therapy for peripheral arterial disease: A double blind, placebo-controlled, randomized trial of HeartBar. Vasc Med 2000, 5:11–19.

    PubMed  CAS  Google Scholar 

  86. Drexler H, et al.: Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology. Circulation 1994, 89:1615–1623.

    PubMed  CAS  Google Scholar 

  87. Drexler H, 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 

  88. Hirooka Y, et al.: Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 1994, 90:658–668.

    PubMed  CAS  Google Scholar 

  89. Otsuji S, et al.: Attenuation of acetylcholine-induced vasoconstriction by L-arginine is related to the progression of atherosclerosis. Am Heart J 1995, 129:1094–1100.

    Article  PubMed  CAS  Google Scholar 

  90. Blum A, et al.: Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women. J Am Coll Cardiol 2000, 35:271–276.

    Article  PubMed  CAS  Google Scholar 

  91. Boger R, et al.: Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997, 95:2068–2074.

    PubMed  CAS  Google Scholar 

  92. Gryglewski RJ, et al.: Treatment with L-arginine is likely to stimulate generation of nitric oxide in patients with peripheral arterial obstructive disease. Wien Klin Wochenschr 1996, 108:111–116.

    PubMed  CAS  Google Scholar 

  93. Schellong SM, et al.: Dose-related effect of intravenous L-arginine on muscular blood flow of the calf in patients with peripheral vascular disease: a H215O positron emission tomography study. Clin Sci 1997, 93:159–165.

    PubMed  CAS  Google Scholar 

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  1. Section of Vascular Medicine, Stanford University School of Medicine, CVRB Section, Floor South, 94305-5406, Stanford, CA, USA

    John P. Cooke MD & Roberta K. Oka RN

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  1. John P. Cooke MD
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Cooke, J.P., Oka, R.K. Atherogenesis and the arginine hypothesis. Curr Atheroscler Rep 3, 252–259 (2001). https://doi.org/10.1007/s11883-001-0068-x

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