Dimethylarginine dimethylaminohydrolase regulation: A novel therapeutic target in cardiovascular disease

Expert Opinion on Drug Metabolism and Toxicology

Volumn 5, Issue 3, 2009, Pages 303-319

  Wadham, Carol ^a,b   Mangoni, Arduino A ^a,b  

^a FLINDERS UNIVERSITY   (Australia)

^b FLINDERS UNIVERSITY   (Australia)

Author keywords

Asymmetric dimethylarginine; Atherosclerosis; Dimethylarginine dimethylaminohydrolase; Endothelium; Nitric oxide

Indexed keywords

ACETYLSALICYLIC ACID; ADIPONECTIN; ALPHA TOCOPHEROL; AMINOGUANIDINE; ATORVASTATIN; CATECHIN; DIMETHYLARGININASE; EDETIC ACID; EPIGALLOCATECHIN; EPIGALLOCATECHIN GALLATE; ESTRADIOL; ESTROGEN; FENOFIBRATE; FLUINDOSTATIN; INSULIN; LOSARTAN; N(G),N(G) DIMETHYLARGININE; NEBIVOLOL; NITRIC OXIDE; PIOGLITAZONE; PRAVASTATIN; PROBUCOL; RETINOIC ACID; RETINOID; RETINOL; SIMVASTATIN; TAURINE; TELMISARTAN; UNINDEXED DRUG; XANTHONE DERIVATIVE; AMIDASE; ARGININE; CARDIOVASCULAR AGENT; DRUG DERIVATIVE; N,N DIMETHYLARGININE; N,N-DIMETHYLARGININE;

ATHEROSCLEROSIS; BLOOD VESSEL INJURY; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DIABETES MELLITUS; DISEASE MODEL; DRUG EFFECT; DRUG TARGETING; ENZYME ACTIVITY; ENZYME REGULATION; HEART FAILURE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; LOW DRUG DOSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PROTEIN EXPRESSION; REVIEW; ANIMAL; DISEASE COURSE; DRUG DELIVERY SYSTEM; GENE EXPRESSION REGULATION; METABOLISM; PATHOPHYSIOLOGY;

AMIDOHYDROLASES; ANIMALS; ARGININE; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; DISEASE PROGRESSION; DRUG DELIVERY SYSTEMS; GENE EXPRESSION REGULATION, ENZYMOLOGIC; HUMANS; NITRIC OXIDE;

EID: 65549089025     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425250902785172     Document Type: Review

References (165)

1. Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol 2002;53:503-514 (Pubitemid 36014797)
2. Ignarro LJ, Napoli C. Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis. Curr Atheroscler Rep 2004;6:281-287 (Pubitemid 39359467)
3. Wilkinson IB, Franklin SS, Cockcroft JR. Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology. Hypertension 2004;44:112-116 (Pubitemid 39014221)
4. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimeth ylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004;24:1023-1030 (Pubitemid 38737826)
5. Cooke JP. ADMA: its role in vascular disease. Vasc Med 2005;10(Suppl 1):S11-7
6. Kielstein JT, Donnerstag F, Gasper S, et al. ADMA increases arterial stiffness and decreases cerebral blood flow in humans. Stroke 2006;37:2024-2029 (Pubitemid 44309898)
7. Zhang GG, Bai YP, Chen MF, et al. Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C. Vasc Pharmacol 2008;48:115-121
8. Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 1989;264:10205-10209 (Pubitemid 19159295)
9. Leiper JM, Santa MJ, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999;343(Pt 1):209-214 (Pubitemid 29473897)
10. Nijveldt RJ, Teerlink T, van Guldener C, et al. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol Dial Transplant 2003;18:2542-2550 (Pubitemid 37483787)
11. Nijveldt RJ, Teerlink T, Siroen MP, et al. The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 2003;22:17-22 (Pubitemid 36193176)
12. Tran CT, Fox MF, Vallance P, Leiper JM. Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 2000;68:101-105
13. Dayoub H, Achan V, Adimoolam S, et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003;108:3042-3047 (Pubitemid 37553576)
14. Dayoub H, Rodionov R, Lynch C, et al. Overexpression of dimethylarginine dimethylaminohydrolase inhibits asymmetric dimethylarginine-induced endothelial dysfunction in the cerebral circulation. Stroke 2008;39:180-184
15. Teerlink T. ADMA metabolism and clearance. Vasc Med 2005;10(Suppl 1):S73-81 (Pubitemid 43137270)
16. Murray-Rust J, Leiper J, McAlister M, et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nat Struct Biol 2001;8:679-683 (Pubitemid 32757926)
17. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci USA 2002;99:13527-13532 (Pubitemid 35215415)
18. Vallance P, Leone A, Calver A, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. lancet 1992;339:572-575
19. 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 Commun 1987;148:671-677
20. Tain YL, Baylis C. Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Kidney Int 2007;72:886-889 (Pubitemid 47462078)
21. Stone EM, Person MD, Costello NJ, Fast W. Characterization of a transient covalent adduct formed during dimethylarginine dimethylaminohydrolase catalysis. Biochemistry 2005;44:7069-7078 (Pubitemid 40632424)
22. Knipp M, Vasak M. A colorimetric 96-well microtiter plate assay for the determination of enzymatically formed citrulline. Anal Biochem 2000;286:257-264 (Pubitemid 30842495)
23. Chobanyan K, Thum T, Suchy MT, et al. GC-MS assay for hepatic DDAH activity in diabetic and non-diabetic rats by measuring dimethylamine (DMA) formed from asymmetric dimethylarginine (ADMA): evaluation of the importance of S-nitrosothiols as inhibitors of DDAH activity in vitro and in vivo in humans. J Chromatogr B Analyt Technol Biomed life Sci 2007;858:32-41 (Pubitemid 47513589)
24. Jiang DJ, Hu GY, Jiang JL, et al. Relationship between protective effect of xanthone on endothelial cells and endogenous nitric oxide synthase inhibitors. Bioorg Med Chem 2003;11:5171-5177 (Pubitemid 37353003)
25. Maas R, Tan-Andreesen J, Schwedhelm E, et al. A stable-isotope based technique for the determination of dimethylarginine dimethylaminohydrolase (DDAH) activity in mouse tissue. J Chromatogr B Analyt Technol Biomed life Sci 2007;851:220-228 (Pubitemid 46720143)
26. Sasaki A, Doi S, Mizutani S, Azuma H. Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats. Am J Physiol lung Cell Mol Physiol 2007;292:l1480-7 (Pubitemid 47077365)
27. Prescott LM, Jones ME. Modified methods for the determination of carbamyl aspartate. Anal Biochem 1969;32:408-419
28. Hong L, Fast W. Inhibition of human dimethylarginine dimethylaminohydrolase-1 by S-nitroso-L-homocysteine and hydrogen peroxide. Analysis, quantification, and implications for hyperhomocysteinemia. J Biol Chem 2007;282:34684-34692 (Pubitemid 350232428)
29. Chen BM, Xia LW, Zhao RQ. Determination of N(G),N(G)-dimethylarginine in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997;692:467-471 (Pubitemid 27217852)
30. Pettersson A, Uggla L, Backman V. Determination of dimethylated arginines in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997;692:257-262 (Pubitemid 27217827)
31. 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 (Pubitemid 28509278)
32. Siroen MP, Teerlink T, Bolte AC, et al. No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia. Gynecol Obstet Invest 2006;62:7-13 (Pubitemid 43999337)
33. Lin KY, Ito A, Asagami T, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002;106:987-992 (Pubitemid 34925335)
34. Ellger B, Richir MC, van Leeuwen PA, et al. Glycemic control modulates arginine and asymmetrical-dimethylarginine levels during critical illness by preserving dimethylarginine-dimethylaminohydrolase activity. Endocrinology 2008;149:3148-3157 (Pubitemid 351724509)
35. Wang L, Zhou Y, Peng J, et al. Role of endogenous nitric oxide synthase inhibitor in gastric mucosal injury. Can J Physiol Pharmacol 2008;86:97-104
36. Tan B, Jiang DJ, Huang H, et al. Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway. Vasc Pharmacol 2007;46:338-345 (Pubitemid 46386501)
37. Bulau P, Zakrzewicz D, Kitowska K, et al. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol lung Cell Mol Physiol 2007;292:l18-24 (Pubitemid 46103426)
38. Jiang DJ, Jia SJ, Yan J, et al. Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction. Biochem Biophys Res Commun 2006;349:683-693 (Pubitemid 44344570)
39. Tang WJ, Hu CP, Chen MF, et al. Epigallocatechin gallate preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level. Can J Physiol Pharmacol 2006;84:163-171 (Pubitemid 43901424)
40. Scalera F, Kielstein JT, Martens-Lobenhoffer J, et al. Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol 2005;16:892-898 (Pubitemid 41710299)
41. Deng S, Deng PY, Jiang JL, et al. Aspirin protected against endothelial damage induced by LDL: role of endogenous NO synthase inhibitors in rats. Acta Pharmacol Sin 2004;25:1633-1639 (Pubitemid 39628031)
42. Jiang DJ, Jiang JL, Zhu HQ, et al. Demethylbellidifolin preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level. J Ethnopharmacol 2004;93:295-306 (Pubitemid 38962420)
43. Zhang WZ, Kaye DM. Simultaneous determination of arginine and seven metabolites in plasma by reversed-phase liquid chromatography with a time-controlled ortho-phthaldialdehyde precolumn derivatization. Anal Biochem 2004;326:87-92 (Pubitemid 38177486)
44. Ueda S, Kato S, Matsuoka H, et al. Regulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine: role of dimethylarginine dimethylaminohydrolase. Circ Res 2003;92:226-233 (Pubitemid 36254279)
45. Krzyzanowska K, Mittermayer F, Wolzt M, Schernthaner G. Asymmetric dimethylarginine predicts cardiovascular events in patients with type 2 diabetes. Diabetes Care 2007;30:1834-1839 (Pubitemid 47036360)
46. Hermenegildo C, Medina P, Peiro M, et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J Clin Endocrinol Metab 2002;87:5636-5640 (Pubitemid 36034371)
47. Billecke SS, Kitzmiller LA, Northrup JJ, et al. Contribution of whole blood to the control of plasma asymmetrical dimethylarginine. Am J Physiol Heart Circ Physiol 2006;291:H1788-96 (Pubitemid 44497685)
48. Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA. Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem 2002;303:131-137 (Pubitemid 34407576)
49. Eid HM, Lyberg T, Arnesen H, Seljeflot I. Insulin and adiponectin inhibit the TNFalpha-induced ADMA accumulation in human endothelial cells: the role of DDAH. Atherosclerosis 2007;194:e1-8 (Pubitemid 47513102)
50. Martens-Lobenhoffer J, Bode-Boger SM. Simultaneous detection of arginine, asymmetric dimethylarginine, symmetric dimethylarginine and citrulline in human plasma and urine applying liquid chromatography-mass spectrometry with very straightforward sample preparation. J Chromatogr B Analyt Technol Biomed life Sci 2003;798:231-239 (Pubitemid 37487722)
51. Martens-Lobenhoffer J, Bode-Boger SM. Fast and efficient determination of arginine, symmetric dimethylarginine, and asymmetric dimethylarginine in biological fluids by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry. Clin Chem 2006;52:488-493 (Pubitemid 43306474)
52. Schwedhelm E. Quantification of ADMA: analytical approaches. Vasc Med 2005;10(Suppl 1):S89-95 (Pubitemid 43137272)
53. Loyaga-Rendon RY, Sakamoto S, Beppu M, et al. Accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, attenuated dimethylarginine dimethylaminohydrolase activity and intimal hyperplasia in premenopausal human uterine arteries. Atherosclerosis 2005;178:231-239 (Pubitemid 40193435)
54. Mizuno Y, Isotani E, Ohno K, et al. Involvement of accumulated NOS inhibitors and endothelin-1, enhanced arginase, and impaired DDAH activities in pulmonary dysfunction following subarachnoid hemorrhage in the rabbit. Vasc Pharmacol 2008;48:21-31
55. Imamura M, Waseda Y, Marinova GV, et al. Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract. Am J Physiol Regul Integr Comp Physiol 2007;293:R2081-9 (Pubitemid 350089890)
56. Schulze F, Wesemann R, Schwedhelm E, et al. Determination of asymmetric dimethylarginine (ADMA) using a novel ElISA assay. Clin Chem Lab Med 2004;42:1377-1383 (Pubitemid 40057825)
57. Konukoglu D, Firtina S, Serin O. The relationship between plasma asymmetrical dimethyl-L-arginine and inflammation and adhesion molecule levels in subjects with normal, impaired, and diabetic glucose tolerance. Metabolism 2008;57:110-115 (Pubitemid 350234980)
58. Blackwell S, O'Reilly DS, Talwar D. Biological variation of asymmetric dimethylarginine and related arginine metabolites and analytical performance goals for their measurement in human plasma. Eur J Clin Invest 2007;37:364-371 (Pubitemid 46653140)
59. Valtonen P, Karppi J, Nyyssonen K, et al. Comparison of HPLC method and commercial ELISA assay for asymmetric dimethylarginine (ADMA) determination in human serum. J Chromatogr B Analyt Technol Biomed Life Sci 2005;828:97-102 (Pubitemid 41735305)
60. Knipp M, Charnock JM, Garner CD, Vasak M. Structural and functional characterization of the Zn(II) site in dimethylargininase-1 (DDAH-1) from bovine brain. Zn(II) release activates DDAH-1. J Biol Chem 2001;276:40449-40456 (Pubitemid 37373183)
61. Frey D, Braun O, Briand C, et al. Structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase: a basis for the design of specific inhibitors. Structure 2006;14:901-911 (Pubitemid 43674095)
62. Knipp M, Braun O, Gehrig PM, et al. Zn(II)-free dimethylargininase-1 (DDAH-1) is inhibited upon specific Cys-S-nitrosylation. J Biol Chem 2003;278:3410-3416 (Pubitemid 36801257)
63. Braun O, Knipp M, Chesnov S, Vasak M. Specific reactions of S-nitrosothiols with cysteine hydrolases: a comparative study between dimethylargininase-1 and CTP synthetase. Protein Sci 2007;16:1522-1534 (Pubitemid 47195680)
64. Maret W. Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 2006;8:1419-1441 (Pubitemid 44726320)
65. Kang ES, Cates TB, Harper DN, et al. An enzyme hydrolyzing methylated inhibitors of nitric oxide synthase is present in circulating human red blood cells. Free Radic Res 2001;35:693-707 (Pubitemid 34065660)
66. Simons TJ. Intracellular free zinc and zinc buffering in human red blood cells. J Membr Biol 1991;123:63-71
67. Achan V, Tran CT, Arrigoni F, et al. all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res 2002;90:764-769 (Pubitemid 34633891)
68. Garbin U, Pasini AF, Stranieri C, et al. Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity. Pharmacol Res 2007;56:515-521 (Pubitemid 350137774)
69. Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 1999;43:542-548 (Pubitemid 29369253)
70. Jones LC, Tran CT, leiper JM, et al. Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem Biophys Res Commun 2003;310:836-843
71. Wakino S, Hayashi K, Tatematsu S, et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens Res 2005;28:255-262 (Pubitemid 40812611)
72. Scalera F, Martens-lobenhoffer J, Bukowska A, et al. Effect of telmisartan on nitric oxide-asymmetrical dimethylarginine system: role of angiotensin II type 1 receptor gamma and peroxisome proliferator activated receptor gamma signaling during endothelial aging. Hypertension 2008;51:696-703 (Pubitemid 351301523)
73. Monsalve E, Oviedo PJ, Garcia-Perez MA, et al. Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells. Cardiovasc Res 2007;73:66-72 (Pubitemid 44937184)
74. Charitidou C, Farmakiotis D, Zournatzi V, et al. The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome. Atherosclerosis 2008;196:958-965
75. Post MS, Verhoeven MO, van der Mooren MJ, et al. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women. J Clin Endocrinol Metab 2003;88:4221-4226 (Pubitemid 37153723)
76. Teerlink T, Neele SJ, de Jong S, et al. Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clin Sci (Lond) 2003;105:67-71 (Pubitemid 36819578)
77. Verhoeven MO, Hemelaar M, van der Mooren MJ, et al. Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study. J Intern Med 2006;259:199-208
78. Holden DP, Cartwright JE, Nussey SS, Whitley GS. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation 2003;108:1575-1580 (Pubitemid 37187783)
79. Pan J, Baker KM. Retinoic acid and the heart. Vitam Horm 2007;75:257-283
80. Choudhary R, Palm-Leis A, Scott RC III, et al. All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system. Am J Physiol Heart Circ Physiol 2008;294:H633-44 (Pubitemid 351253274)
81. Wang HJ, Zhu YC, Yao T. Effects of all-trans retinoic acid on angiotensin II-induced myocyte hypertrophy. J Appl Physiol 2002;92:2162-2168 (Pubitemid 34666447)
82. Bjelakovic G, Nikolova D, Gluud LL, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2008;CD007176 (Pubitemid 351807478)
83. Munteanu A, Zingg JM. Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention. Mol Aspects Med 2007;28:538-590 (Pubitemid 47628863)
84. Onozato ML, Tojo A, leiper J, et al. Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers. Diabetes 2008;57:172-180
85. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo italiano per lo studio della sopravvivenza nell'infarto miocardico. lancet 1999;354:447-455
86. Wang Y, Shi JG, Wang MZ, et al. Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. life Sci 2008;82:91-98
87. Dai Z, Jiang DJ, Hu GY, et al. 3,4,5,6-Tetrahydroxyxanthone protects against myocardial ischemia-reperfusion injury in rats. Cardiovasc Drugs Ther 2004;18:279-288
88. Madan B, Prasad AK, Parmar VS, Ghosh B. 1,4-dihydroxyxanthone modulates the adhesive property of endothelial cells by inhibiting intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Bioorg Med Chem 2004;12:1431-1437
89. Rosendorff C. Effects of LDL cholesterol on vascular function. J Hum Hypertens 2002;16(Suppl 1):S26-8 (Pubitemid 34441131)
90. Babu PV, liu D. Green tea catechins and cardiovascular health: an update. Curr Med Chem 2008;15:1840-1850
91. Widlansky ME, Hamburg NM, Anter E, et al. Acute EGCG supplementation reverses endothelial dysfunction in patients with coronary artery disease. J Am Coll Nutr 2007;26:95-102 (Pubitemid 46911252)
92. Nagao T, Hase T, Tokimitsu I. A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring) 2007;15:1473-1483
93. Militante JD, Lombardini JB. Treatment of hypertension with oral taurine: experimental and clinical studies. Amino Acids 2002;23:381-393 (Pubitemid 35435596)
94. Steinberg HO, Baron AD. Insulin-dependent diabetes mellitus and nitrovasodilation. Important and complex interactions. Circulation 1997;95:560-561
95. Beltowski J, Jamroz-Wisniewska A, Widomska S. Adiponectin and its role in cardiovascular diseases. Cardiovasc Hematol Disord Drug Targets 2008;8:7-46
96. Despres JP, Lemieux I, Bergeron J, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008;28:1039-1049
97. Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for diabetic nephropathy. Expert Opin Investig Drugs 2002;11:565-574
98. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 2001;357:593-615 (Pubitemid 32735142)
99. Su J, Lucchesi PA, Gonzalez-Villalobos RA, et al. Role of advanced glycation end products with oxidative stress in resistance artery dysfunction in type 2 diabetic mice. Arterioscler Thromb Vasc Biol 2008;28:1432-1438
100. Yin QF, Fu SH, He P, Xiong Y. Dimethylarginine dimethylaminohydrolase inhibition and asymmetric dimethylarginine accumulation contribute to endothelial dysfunction in rats exposed to glycosylated protein: effects of aminoguanidine. Atherosclerosis 2007;190:53-61 (Pubitemid 44908321)
101. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004;24:32-40 (Pubitemid 38250484)
102. Arnal JF, Douin-Echinard V, Brouchet L, et al. Understanding the oestrogen action in experimental and clinical atherosclerosis. Fundam Clin Pharmacol 2006;20:539-548 (Pubitemid 44760173)
103. Qiao X, McConnell KR, Khalil RA. Sex steroids and vascular responses in hypertension and aging. Gend Med 2008;5(Suppl A):S46-64
104. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-941 (Pubitemid 32003509)
105. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial. JAMA 2002;288:321-333 (Pubitemid 34761611)
106. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and estrogen/progestin replacement study (HERS) research group. JAMA 1998;280:605-613 (Pubitemid 28502636)
107. Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 2002;53:605-619 (Pubitemid 34175253)
108. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86 (Pubitemid 34073138)
109. Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol 2005;46:1425-1433 (Pubitemid 41446176)
110. Chen YH, Lin SJ, Chen YL, et al. Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules. Cardiovasc Hematol Disord Drug Targets 2006;6:279-304 (Pubitemid 44890589)
111. Tsimihodimos V, Miltiadous G, Daskalopoulou SS, et al. Fenofibrate: metabolic and pleiotropic effects. Curr Vasc Pharmacol 2005;3:87-98 (Pubitemid 40089531)
112. Yin QF, Xiong Y. Pravastatin restores DDAH activity and endothelium-dependent relaxation of rat aorta after exposure to glycated protein. J Cardiovasc Pharmacol 2005;45:525-532 (Pubitemid 40734572)
113. Yang TL, Chen MF, Luo BL, et al. Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-kappaB activity. Naunyn Schmiedebergs Arch Pharmacol 2005;371:401-407 (Pubitemid 41187512)
114. Jiang JL, Zhang XH, Li NS, et al. Probucol decreases asymmetrical dimethylarginine level by alternation of protein arginine methyltransferase I and dimethylarginine dimethylaminohydrolase activity. Cardiovasc Drugs Ther 2006;20:281-294 (Pubitemid 44701162)
115. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. lancet 2002;360:1623-1630
116. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004;110:1557-1563 (Pubitemid 39297976)
117. Ford I, Murray H, Packard CJ, et al. long-term follow-up of the West of scotland coronary prevention study. N Engl J Med 2007;357:1477-1486 (Pubitemid 47572633)
118. Scott R, O'brien R, Fulcher G, et al. The effects of fenofibrate treatment on cardiovascular disease risk in 9795 people with type 2 diabetes and various components of the metabolic syndrome: the FIElD study. Diabetes Care 2009;32:493-498
119. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIElD study): randomised controlled trial. lancet 2005;366:1849-1861
120. Tanaka N, Katayama Y, Katsumata T, et al. Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats. Brain Res 2007;1169:125-132 (Pubitemid 47381354)
121. Young JM, Strey CH, George PM, et al. Effect of atorvastatin on plasma levels of asymmetric dimethylarginine in patients with non-ischaemic heart failure. Eur J Heart Fail 2008;10:463-466
122. Santilli F, Bucciarelli L, Noto D, et al. Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins. Free Radic Biol Med 2007;43:1255-1262 (Pubitemid 47429934)
123. Shinohara K, Shoji T, Kimoto E, et al. Effect of atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. J Atheroscler Thromb 2005;12:205-210
124. Valkonen VP, laakso J, Paiva H, et al. Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels? Atheroscler Suppl 2003;4:19-22
125. Paiva H, Laakso J, Lehtimaki T, et al. Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors. J Cardiovasc Pharmacol 2003;41:219-222 (Pubitemid 36135246)
126. Panichi V, Mantuano E, Paoletti S, et al. Effect of simvastatin on plasma asymmetric dimethylarginine concentration in patients with chronic kidney disease. J Nephrol 2008;21:38-44 (Pubitemid 351780572)
127. Boger GI, Rudolph TK, Maas R, et al. Asymmetric dimethylarginine determines the improvement of endotheliumdependent vasodilation by simvastatin: effect of combination with oral l-arginine. J Am Coll Cardiol 2007;49:2274-2282 (Pubitemid 46856823)
128. Pereira EC, Bertolami MC, Faludi AA, et al. Effects of simvastatin and L-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects. Free Radic Res 2003;37:529-536 (Pubitemid 36410894)
129. Janatuinen T, Laakso J, Laaksonen R, et al. Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults. Vasc Med 2003;8:185-189 (Pubitemid 38220196)
130. Oguz A, Uzunlulu M. Short term fluvastatin treatment lowers serum asymmetric dimethylarginine levels in patients with metabolic syndrome. Int Heart J 2008;49:303-311
131. Pat B, Yang T, Kong C, et al. Activation of ERK in renal fibrosis after unilateral ureteral obstruction: modulation by antioxidants. Kidney Int 2005;67:931-943 (Pubitemid 41623317)
132. Yamaguchi Y, Matsuno S, Kagota S, et al. Fluvastatin reduces modification of low-density lipoprotein in hyperlipidemic rabbit loaded with oxidative stress. Eur J Pharmacol 2002;436:97-105 (Pubitemid 34142403)
133. Nagase S, Hirayama A, Ueda A, et al. Does fluvastatin really have an antioxidant effect in humans? Kidney Int 2005;68:1373-1374
134. Gupta S, Wright HM. Nebivolol: a highly selective beta1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther 2008;26:189-202
135. Pasini AF, Garbin U, Stranieri C, et al. Nebivolol treatment reduces serum levels of asymmetric dimethylarginine and improves endothelial dysfunction in essential hypertensive patients. Am J Hypertens 2008;21:1251-1257
136. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-225 (Pubitemid 40222359)
137. Chrysant SG, Chrysant GS. The pleiotropic effects of angiotensin receptor blockers. J Clin Hypertens 2006;8:261-268
138. Chen MF, Xie XM, Yang TL, et al. Role of asymmetric dimethylarginine in inflammatory reactions by angiotensin II. J Vasc Res 2007;44:391-402 (Pubitemid 47312660)
139. Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002;288:1491-1498 (Pubitemid 35052200)
140. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559
141. Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension 2002;40:687-693 (Pubitemid 35282444)
142. Majithiya JB, Paramar AN, Balaraman R. Pioglitazone, a PPARgamma agonist, restores endothelial function in aorta of streptozotocin-induced diabetic rats. Cardiovasc Res 2005;66:150-161 (Pubitemid 40357878)
143. Buchanan TA, Meehan WP, Jeng YY, et al. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995;96:354-360
144. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-1554 (Pubitemid 40923063)
145. Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299:1561-1573
146. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296:2572-2581 (Pubitemid 44903861)
147. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-1289 (Pubitemid 41416583)
148. Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298:2634-2643 (Pubitemid 350254955)
149. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189-1195 (Pubitemid 47403105)
150. Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 2000;28:149-167 (Pubitemid 30648951)
151. Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 2007;293:H3227-45 (Pubitemid 350230862)
152. Dayal S, Rodionov RN, Arning E, et al. Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia. Am J Physiol Heart Circ Physiol 2008;295:H816-25
153. Boyde TR, Rahmatullah M. Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime. Anal Biochem 1980;107:424-431 (Pubitemid 11220248)
154. Nonaka S, Tsunoda M, Aoyama C, Funatsu T. Determination of NG, NG-dimethyl-L-arginine in rat plasma and dimethylarginine dimethylaminohydrolase activity in rat kidney using a monolithic silica column. J Chromatogr B Analyt Technol Biomed life Sci 2006;843:170-174 (Pubitemid 44636420)
155. MacAllister RJ, Rambausek MH, Vallance P, et al. Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant 1996;11:2449-2452 (Pubitemid 27033779)
156. MacAllister RJ, Fickling SA, Whitley GS, Vallance P. Metabolism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis. Br J Pharmacol 1994;112:43-48 (Pubitemid 24151701)
157. Ito A, Tsao PS, Adimoolam S, et al. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99:3092-3095 (Pubitemid 29289071)
158. Bogumil R, Knipp M, Fundel SM, Vasak M. Characterization of dimethylargininase from bovine brain: evidence for a zinc binding site. Biochemistry 1998;37:4791-4798 (Pubitemid 28175959)
159. Stuhlinger MC, Tsao PS, Her JH, et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001;104:2569-2575 (Pubitemid 33104795)
160. Jia SJ, Jiang DJ, Hu CP, et al. lysophosphatidylcholine-induced elevation of asymmetric dimethylarginine level by the NADPH oxidase pathway in endothelial cells. Vasc Pharmacol 2006;44:143-148 (Pubitemid 43183662)
161. Rossiter S, Smith CL, Malaki M, et al. Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase. J Med Chem 2005;48:4670-4678 (Pubitemid 40993426)
162. Xin HY, Jiang DJ, Jia SJ, et al. Regulation by DDAH/ADMA pathway of lipopolysaccharide-induced tissue factor expression in endothelial cells. Thromb Haemost 2007;97:830-838 (Pubitemid 46779968)
163. Leiper J, Nandi M, Torondel B, et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 2007;13:198-203 (Pubitemid 46245768)
164. Forbes SP, Druhan LJ, Guzman JE, et al. Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulation. Biochemistry 2008;47:1819-1826 (Pubitemid 351231231)
165. Zhang GG, Shi RZ, Jiang DJ, et al. Involvement of the endothelial DDAH/ADMA pathway in nitroglycerin tolerance: the role of AlDH-2. life Sci 2008;82:699-707