© 2000 American Heart Association, Inc.
Vascular Biology |
Homocysteine-Induced Inhibition of Endothelium-Dependent Relaxation in Rabbit Aorta
Role for Superoxide Anions
From the Cardiovascular Sciences Research Group, Departments of Pharmacology, Therapeutics, and Toxicology (D.L., M.B.K., S.A.H., C.A.P., M.J.L.) and Cardiology (M.F.B.), University of Wales College of Medicine, Heath Park, Cardiff, UK, and the Division of Child Health (S.J.M., H.J.P.), University of Sheffield, Sheffield Children’s Hospital, Western Bank, Sheffield, UK.
Correspondence to Dr D. Lang, Department of Pharmacology, Therapeutics, and Toxicology, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, UK. Email langd{at}cf.ac.uk
Abstract—Hyperhomocysteinemia is associated with endothelial dysfunction, although its mechanism is unknown. Isometric tension recordings and lucigenin chemiluminescence were used to assess the effects of homocysteine exposure on endothelium-dependent and -independent relaxation in isolated rabbit aortic rings and superoxide anion (O2-) production by cultured porcine aortic endothelial cells, respectively. Homocysteine (0.1 to 10 mmol/L) produced a significant (P<0.001) concentration- and time-dependent inhibition of endothelium-dependent relaxation in response to both acetylcholine and the calcium ionophore A23187. Only the intracellular O2- scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron, 10 mmol/L) significantly (P<0.001) inhibited the effect of homocysteine on acetylcholine- and A23187-induced relaxation. Incubation of porcine aortic endothelial cells with homocysteine (0.03 to 1 mmol/L for up to 72 hours) caused a significant (P<0.001) time-dependent increase in the O2- released by these cells on the addition of Triton X-100 (1% [vol/vol]), with levels returning to values comparable to those of control cells at the 72-hour time point. These changes in O2- levels were associated with a time-dependent increase in endothelial cell superoxide dismutase activity, becoming significant (P<0.001) after 72 hours. Furthermore, the homocysteine-induced increase in endothelial cell O2- levels was completely inhibited (P<0.001) by the concomitant incubation with either Tiron (10 mmol/L), vitamin C (10 µmol/L), or vitamin E (10 µmol/L). These data suggest that the inhibitory effect of homocysteine on endothelium-dependent relaxation is due to an increase in the endothelial cell intracellular levels of O2- and provide a possible mechanism for the endothelial dysfunction associated with hyperhomocysteinemia.
Key Words: homocysteine • endothelial function • nitric oxide • oxygen-derived free radicals
This article has been cited by other articles:
 |
|
 |
|
  S. Dayal and S. R. Lentz Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1596 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Suematsu, C. Ojaimi, S. Kinugawa, Z. Wang, X. Xu, A. Koller MD, F. A. Recchia, and T. H. Hintze Hyperhomocysteinemia Alters Cardiac Substrate Metabolism by Impairing Nitric Oxide Bioavailability Through Oxidative Stress Circulation, January 16, 2007; 115(2): 255 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Colgan and R. C. Austin Homocysteinylation of Metallothionein Impairs Intracellular Redox Homeostasis: The Enemy Within! Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 8 - 11. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Carrasco-Pozo, A. Alvarez-Lueje, C. Olea-Azar, C. Lopez-Alarcon, and H. Speisky In vitro interaction between homocysteine and copper ions: potential redox implications. Experimental Biology and Medicine, October 1, 2006; 231(9): 1569 - 1575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Symons, J. C. Rutledge, U. Simonsen, and R. A. Pattathu Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H181 - H191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bosch-Marce, R. Pola, A. B Wecker, M. Silver, A. Weber, C. Luedemann, C. Curry, T. Murayama, M. Kearney, Y.-s. Yoon, et al. Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia Vascular Medicine, February 1, 2005; 10(1): 15 - 22. [Abstract] [PDF]
|
|
|
|
|
|
C. W. van den Berg, K. E. Taylor, and D. Lang C-Reactive Protein-Induced In Vitro Vasorelaxation Is an Artefact Caused by the Presence of Sodium Azide in Commercial Preparations Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): e168 - e171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. De Young, D. Yu, R. M. Bateman, and G. B. Brock Oxidative Stress and Antioxidant Therapy: Their Impact in Diabetes-Associated Erectile Dysfunction J Androl, September 1, 2004; 25(5): 830 - 836. [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]
|
|
|
|
|
|
Z. Bagi, C. Cseko, E. Toth, and A. Koller Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2277 - H2283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zulli, R. E. Widdop, D. L. Hare, B. F. Buxton, and M. J. Black High Methionine and Cholesterol Diet Abolishes Endothelial Relaxation Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1358 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Virdis, M. Iglarz, M. F. Neves, F. Amiri, R. M. Touyz, R. Rozen, and E. L. Schiffrin Effect of Hyperhomocystinemia and Hypertension on Endothelial Function in Methylenetetrahydrofolate Reductase-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1352 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sebekova, M. Krajcovicova-Kudlackova, P. Blazicek, V. Parrak, R. Schinzel, and A. Heidland Functional Hyperhomocysteinemia in Healthy Vegetarians: No Association with Advanced Glycation End Products, Markers of Protein Oxidation, or Lipid Peroxidation after Correction with Vitamin B12 Clin. Chem., June 1, 2003; 49(6): 983 - 986. [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Shi, J. E. Savage, S. J. Hufeisen, L. Rauser, E. Grajkowska, P. Ernsberger, J. T. Wroblewski, J. H. Nadeau, and B. L. Roth L-Homocysteine Sulfinic Acid and Other Acidic Homocysteine Derivatives Are Potent and Selective Metabotropic Glutamate Receptor Agonists J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 131 - 142. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. Ay, E. M. Arsava, S. L. Tokgozoglu, N. Ozer, and O. Saribas Hyperhomocysteinemia Is Associated With the Presence of Left Atrial Thrombus in Stroke Patients With Nonvalvular Atrial Fibrillation Stroke, April 1, 2003; 34(4): 909 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sydow, E. Schwedhelm, N. Arakawa, S. M. Bode-Boger, D. Tsikas, B. Hornig, J. C. Frolich, and R. H. Boger ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins Cardiovasc Res, January 1, 2003; 57(1): 244 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, F.-X. Yi, E. Rute, D. X. Zhang, G. R. Slocum, and A.-P. Zou Effects of homocysteine on intracellular nitric oxide and superoxide levels in the renal arterial endothelium Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1237 - H1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
|
|
|
|
 |
|
 Z. Ungvari, A. Csiszar, Z. Bagi, and A. Koller Impaired Nitric Oxide-Mediated Flow-Induced Coronary Dilation in Hyperhomocysteinemia : Morphological and Functional Evidence for Increased Peroxynitrite Formation Am. J. Pathol., July 1, 2002; 161(1): 145 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zheng, C. Dimayuga, A. Hudaihed, and S. D. Katz Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): e15 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lee and K. Prasad Hyperhomocysteinemia and Venous Thrombosis International Journal of Lower Extremity Wounds, March 1, 2002; 1(1): 4 - 12. [Abstract] [PDF]
|
|
|
|
|
|
Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Stuhlinger, P. S. Tsao, J.-H. Her, M. Kimoto, R. F. Balint, and J. P. Cooke Homocysteine Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine Circulation, November 20, 2001; 104(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Weiss, Y.-Y. Zhang, S. Heydrick, C. Bierl, and J. Loscalzo Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction PNAS, October 12, 2001; (2001) 231428998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Bell, S. I. Mosfer, D. Lang, F. Donaldson, and M. J. Lewis Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1704 - H1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-L. Li, Y.-M. Chao, S. H. H. Chan, and J. Y. H. Chan Potentiation of Baroreceptor Reflex Response by Heat Shock Protein 70 in Nucleus Tractus Solitarii Confers Cardiovascular Protection During Heatstroke Circulation, April 24, 2001; 103(16): 2114 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Morita, H. Kurihara, S. Yoshida, Y. Saito, T. Shindo, Y. Oh-hashi, Y. Kurihara, Y. Yazaki, and R. Nagai Diet-Induced Hyperhomocysteinemia Exacerbates Neointima Formation in Rat Carotid Arteries After Balloon Injury Circulation, January 2, 2001; 103(1): 133 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Jacobsen Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check? Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1182 - 1184. [Full Text] [PDF]
|
|
|
|
|
|
N. Weiss, Y.-Y. Zhang, S. Heydrick, C. Bierl, and J. Loscalzo Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction PNAS, October 23, 2001; 98(22): 12503 - 12508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, S. Brodsky, S. Kumari, V. Valiunas, P. Brink, J.-I. Kaide, A. Nasjletti, and M. S. Goligorsky Paradoxical overexpression and translocation of connexin43 in homocysteine-treated endothelial cells Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2124 - H2133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, A. Lewis, S. Brodsky, R. Rieger, C. Iden, and M. S. Goligorsky Homocysteine Induces 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Vascular Endothelial Cells: A Mechanism for Development of Atherosclerosis? Circulation, March 5, 2002; 105(9): 1037 - 1043. [Abstract] [Full Text] [PDF]
|
|