Circulation. 2002;106:987-992
Published online before print July 29, 2002, doi: 10.1161/01.CIR.0000027109.14149.67
Published online before print July 29, 2002, doi: 10.1161/01.CIR.0000027109.14149.67
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:987.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Impaired Nitric Oxide Synthase Pathway in Diabetes Mellitus
Role of Asymmetric Dimethylarginine and Dimethylarginine Dimethylaminohydrolase
From the Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif (K.Y.L., A.I., T.A., P.S.T., S.A., G.M.R., J.P.C.), and the Department of Nutritional Science, Okayama Prefectural University, Soja, Okayama, Japan (M.K., H.T.).
Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke{at}stanford.edu
Background— An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM.
Methods and Results— Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33±0.31 versus 0.48±0.08 µmol/L; P<0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P<0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol–conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis.
Conclusions— A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.
Key Words: nitric oxide • endothelium • oxidative stress
This article has been cited by other articles:
 |
|
 |
|
  B. Ellger, M. C. Richir, P. A. M. van Leeuwen, Y. Debaveye, L. Langouche, I. Vanhorebeek, T. Teerlink, and G. Van den Berghe Glycemic Control Modulates Arginine and Asymmetrical-Dimethylarginine Levels during Critical Illness by Preserving Dimethylarginine-Dimethylaminohydrolase Activity Endocrinology, June 1, 2008; 149(6): 3148 - 3157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sud, S. M. Wells, S. Sharma, D. A. Wiseman, J. Wilham, and S. M. Black Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: role of mitochondrial dysfunction Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1407 - C1418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lajer, L. Tarnow, A. Jorsal, T. Teerlink, H.-H. Parving, and P. Rossing Plasma Concentration of Asymmetric Dimethylarginine (ADMA) Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients With Diabetic Nephropathy Diabetes Care, April 1, 2008; 31(4): 747 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sydow, C. E. Mondon, J. Schrader, H. Konishi, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 692 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Kashyap, A. Lara, R. Zhang, Y. M. Park, and R. A. DeFronzo Insulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients Diabetes Care, January 1, 2008; 31(1): 134 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Onozato, A. Tojo, J. Leiper, T. Fujita, F. Palm, and C. S. Wilcox Expression of NG,NG-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney: Effects of Angiotensin II Receptor Blockers Diabetes, January 1, 2008; 57(1): 172 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Baylis Nitric oxide deficiency in chronic kidney disease Am J Physiol Renal Physiol, January 1, 2008; 294(1): F1 - F9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Imamura, Y. Waseda, G. V. Marinova, T. Ishibashi, S. Obayashi, A. Sasaki, A. Nagai, and H. Azuma Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R2081 - R2089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden Insulin Resistance, Dyslipidemia, and Cardiovascular Disease Diabetes Care, August 1, 2007; 30(8): 2164 - 2170. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hasegawa, S. Wakino, S. Tatematsu, K. Yoshioka, K. Homma, N. Sugano, M. Kimoto, K. Hayashi, and H. Itoh Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2 Circ. Res., July 20, 2007; 101(2): e2 - e10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Wilson, R. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm Circulation, July 10, 2007; 116(2): 188 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Authors/Task Force Members, L. Ryden, E. Standl, M. Bartnik, G. V. d. Berghe, J. Betteridge, M.-J. de Boer, F. Cosentino, B. Jonsson, M. Laakso, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) Eur. Heart J. Suppl., June 1, 2007; 9(suppl_C): C3 - C74. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sasaki, S. Doi, S. Mizutani, and H. Azuma 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, June 1, 2007; 292(6): L1480 - L1487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Altinova, M. Arslan, A. Sepici-Dincel, M. Akturk, N. Altan, and F. B. Toruner Uncomplicated Type 1 Diabetes Is Associated with Increased Asymmetric Dimethylarginine Concentrations J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1881 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Toth, A. Racz, P. M. Kaminski, M. S. Wolin, Z. Bagi, and A. Koller Asymmetrical Dimethylarginine Inhibits Shear Stress-Induced Nitric Oxide Release and Dilation and Elicits Superoxide-Mediated Increase in Arteriolar Tone Hypertension, March 1, 2007; 49(3): 563 - 568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Monsalve, P. J. Oviedo, M. A. Garcia-Perez, J. J. Tarin, A. Cano, and C. Hermenegildo Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells Cardiovasc Res, January 1, 2007; 73(1): 66 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. V. Fedorova, N. I. Agalakova, C. H. Morrell, E. G. Lakatta, and A. Y. Bagrov ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta Hypertension, December 1, 2006; 48(6): 1160 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mittermayer, K. Krzyzanowska, M. Exner, W. Mlekusch, J. Amighi, S. Sabeti, E. Minar, M. Muller, M. Wolzt, and M. Schillinger Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With Advanced Peripheral Artery Disease Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2536 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Billecke, L. A. Kitzmiller, J. J. Northrup, S. E. Whitesall, M. Kimoto, A. V. Hinz, and L. G. D'Alecy Contribution of whole blood to the control of plasma asymmetrical dimethylarginine Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1788 - H1796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matsuguma, S. Ueda, S.-i. Yamagishi, Y. Matsumoto, U. Kaneyuki, R. Shibata, T. Fujimura, H. Matsuoka, M. Kimoto, S. Kato, et al. Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2176 - 2183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yasuda, S. Miyazaki, M. Kanda, Y. Goto, M. Suzuki, Y. Harano, and H. Nonogi Intensive treatment of risk factors in patients with type-2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase Eur. Heart J., May 2, 2006; 27(10): 1159 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Forstermann and T. Munzel Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace Circulation, April 4, 2006; 113(13): 1708 - 1714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yamamoto and Y. Aso Synergistic Association of Metabolic Syndrome and Overt Nephropathy With Elevated Asymmetric Dimethylarginine in Serum and Impaired Cutaneous Microvasodilation in Patients With Type 2 Diabetes Diabetes Care, April 1, 2006; 29(4): 928 - 930. [Full Text] [PDF]
|
|
|
|
|
|
K. A. Carello, S. E. Whitesall, M. C. Lloyd, S. S. Billecke, and L. G. D'Alecy Asymmetrical dimethylarginine plasma clearance persists after acute total nephrectomy in rats Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H209 - H216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Kawata, M Daimon, R Hasegawa, K Teramoto, T Toyoda, T Sekine, K Yamamoto, D Uchida, T Himi, K Yoshida, et al. Serum asymmetric dimethylarginine as a marker of coronary microcirculation in patients with non-insulin dependent diabetes mellitus: correlation with coronary flow reserve Heart, December 1, 2005; 91(12): 1607 - 1608. [Full Text] [PDF]
|
|
|
|
 |
|
 R. K Oka, A. Szuba, J. C Giacomini, and J. P Cooke A pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease Vascular Medicine, November 1, 2005; 10(4): 265 - 274. [Abstract] [PDF]
|
|
|
|
|
|
F. Palm, D. G. Buerk, P.-O. Carlsson, P. Hansell, and P. Liss Reduced Nitric Oxide Concentration in the Renal Cortex of Streptozotocin-Induced Diabetic Rats: Effects on Renal Oxygenation and Microcirculation Diabetes, November 1, 2005; 54(11): 3282 - 3287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, Y. Li, P. Zhang, J. H. Traverse, M. Hou, X. Xu, M. Kimoto, and R. J. Bache Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2212 - H2219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schnabel, S. Blankenberg, E. Lubos, K. J. Lackner, H. J. Rupprecht, C. Espinola-Klein, N. Jachmann, F. Post, D. Peetz, C. Bickel, et al. Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease: Results from the AtheroGene Study Circ. Res., September 2, 2005; 97(5): e53 - e59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Munzel, A. Daiber, V. Ullrich, and A. Mulsch 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., August 1, 2005; 25(8): 1551 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R307 - R316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Mediators, pediatric insulin resistance, the polycystic ovary syndrome, and malignancy Diabetes Care, July 1, 2005; 28(7): 1821 - 1830. [Full Text] [PDF]
|
|
|
|
|
|
J. Molnar, S. Yu, N. Mzhavia, C. Pau, I. Chereshnev, and H. M. Dansky Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice Circ. Res., June 10, 2005; 96(11): 1178 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. O. Prior, M. J. Quinones, M. Hernandez-Pampaloni, A. D. Facta, T. H. Schindler, J. W. Sayre, W. A. Hsueh, and H. R. Schelbert Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus Circulation, May 10, 2005; 111(18): 2291 - 2298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P Cooke ADMA: its role in vascular disease Vascular Medicine, May 1, 2005; 10(2_suppl): S11 - S17. [Abstract] [PDF]
|
|
|
|
|
|
K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43. [Abstract] [PDF]
|
|
|
|
|
|
R. Maas Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vascular Medicine, May 1, 2005; 10(2_suppl): S49 - S57. [Abstract] [PDF]
|
|
|
|
|
|
S. M Bode-Boger, F. Scalera, and J. Martens-Lobenhoffer Asymmetric dimethylarginine (ADMA) accelerates cell senescence Vascular Medicine, May 1, 2005; 10(2_suppl): S65 - S71. [Abstract] [PDF]
|
|
|
|
|
|
T. Teerlink ADMA metabolism and clearance Vascular Medicine, May 1, 2005; 10(2_suppl): S73 - S81. [Abstract] [PDF]
|
|
|
|
|
|
R. H Boger, E. Schwedhelm, R. Maas, S. Quispe-Bravo, and C. Skamira ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study Vascular Medicine, May 1, 2005; 10(2_suppl): S97 - S102. [Abstract] [PDF]
|
|
|
|
|
|
F. Scalera, J. T. Kielstein, J. Martens-Lobenhoffer, S. C. Postel, M. Tager, and S. M. Bode-Boger Erythropoietin Increases Asymmetric Dimethylarginine in Endothelial Cells: Role of Dimethylarginine Dimethylaminohydrolase J. Am. Soc. Nephrol., April 1, 2005; 16(4): 892 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dandona, A. Aljada, A. Chaudhuri, P. Mohanty, and R. Garg Metabolic Syndrome: A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation Circulation, March 22, 2005; 111(11): 1448 - 1454. [Full Text] [PDF]
|
|
|
|
|
|
V Achan, H. Ho, C Heeschen, M Stuehlinger, J. Jang, M Kimoto, P Vallance, and J. Cooke ADMA regulates angiogenesis: genetic and metabolic evidence Vascular Medicine, February 1, 2005; 10(1): 7 - 14. [Abstract] [PDF]
|
|
|
|
 |
|
 S. C. Tyagi, W. Rodriguez, A. M. Patel, A. M. Roberts, J. C. Falcone, J. C. Passmore, J. T. Fleming, and I. G. Joshua Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 1 - 10. [Abstract] [PDF]
|
|
|
|
 |
|
 B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scalera, J. Borlak, B. Beckmann, J. Martens-Lobenhoffer, T. Thum, M. Tager, and S. M. Bode-Boger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1816 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Gornik and M. A. Creager Arginine and Endothelial and Vascular Health J. Nutr., October 1, 2004; 134(10): 2880S - 2887S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vallance and J. Leiper Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1023 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sydow, B. Hornig, N. Arakawa, S. M Bode-Boger, D. Tsikas, T. Munuzel, and R. H Boger Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA Vascular Medicine, May 1, 2004; 9(2): 93 - 101. [Abstract] [PDF]
|
|
|
|
|
|
J. P. Cooke Asymmetrical Dimethylarginine: The Uber Marker? Circulation, April 20, 2004; 109(15): 1813 - 1818. [Full Text] [PDF]
|
|
|
|
|
|
L. Tarnow, P. Hovind, T. Teerlink, C. D.A. Stehouwer, and H.-H. Parving Elevated Plasma Asymmetric Dimethylarginine as a Marker of Cardiovascular Morbidity in Early Diabetic Nephropathy in Type 1 Diabetes Diabetes Care, March 1, 2004; 27(3): 765 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kohli, C. J. Meininger, T. E. Haynes, W. Yan, J. T. Self, and G. Wu Dietary L-Arginine Supplementation Enhances Endothelial Nitric Oxide Synthesis in Streptozotocin-Induced Diabetic Rats J. Nutr., March 1, 2004; 134(3): 600 - 608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden The 1st World Congress on the Insulin Resistance Syndrome Diabetes Care, February 1, 2004; 27(2): 602 - 609. [Full Text] [PDF]
|
|
|
|
|
|
E. T. Fossel Improvement of Temperature and Flow in Feet of Subjects with Diabetes With Use of a Transdermal Preparation of L-Arginine: A pilot study Diabetes Care, January 1, 2004; 27(1): 284 - 285. [Full Text] [PDF]
|
|
|
|
|
|
H. Dayoub, V. Achan, S. Adimoolam, J. Jacobi, M. C. Stuehlinger, B.-y. Wang, P. S. Tsao, M. Kimoto, P. Vallance, A. J. Patterson, et al. Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence Circulation, December 16, 2003; 108(24): 3042 - 3047. [Abstract] [Full Text] [PDF]
|
|
|
|
|