© 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
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