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 (O 2 Ϫ ) production by cultured porcine aortic endothelial cells, respectively. Homocysteine (0.1 to 10 mmol/L) produced a significant (PϽ0.001) concentration-and time-dependent inhibition of endothelium-dependent relaxation in response to both acetylcholine and the calcium ionophore A23187. Only the intracellular O 2 Ϫ scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron, 10 mmol/L) significantly (PϽ0.001) 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 (PϽ0.001) time-dependent increase in the O 2 Ϫ 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 O 2 Ϫ levels were associated with a time-dependent increase in endothelial cell superoxide dismutase activity, becoming significant (PϽ0.001) after 72 hours. Furthermore, the homocysteine-induced increase in endothelial cell O 2 Ϫ levels was completely inhibited (PϽ0.001) by the concomitant incubation with either Tiron (10 mmol/L), vitamin C (10 mol/L), or vitamin E (10 mol/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 O 2 Ϫ and provide a possible mechanism for the endothelial dysfunction associated with hyperhomocysteinemia. Key Words: homocysteine Ⅲ endothelial function Ⅲ nitric oxide Ⅲ oxygen-derived free radicals D eficiencies in the enzymes cystathionine  synthase and methylenetetrahydrofolate reductase lead to elevated plasma homocyst(e)ine levels (free and bound homocysteine plus homocystine and homocysteine-cysteine mixed disulfide). 1 Patients with these disorders have much higher plasma concentrations of homocysteine than do normal subjects (Ն80 mol/L compared with Յ10 mol/L, respectively) and are prone to premature cardiovascular disease. 2 Severe hyperhomocysteinemia, arising, for example, from cystathionine  synthase deficiency, is rare among the general population, whereas mild hyperhomocysteinemia (15 to 30 mol/L) is common. A recent epidemiological study confirms that even such modestly elevated homocysteine levels are associated with an increased risk of atherosclerosis 3 and can theoretically be caused by reduced activity of the enzyme methylenetetrahydrofolate reductase or deficiencies in folic acid and vitamin B 12 .The mechanism of the vascular injury seen in hyperhomocysteinemia is not known, although growing evidence suggests that endothelial dysfunction plays a major role. 4,5 Indeed, homocystein...
A functional phagocyte-type NADPH oxidase is expressed in coronary microvascular endothelial cells, where it may contribute to the physiological and/or pathophysiological effects of reactive oxygen species. These data, together with reports of the presence of a similar oxidase in other non-phagocytic cell types, suggest that this enzyme complex is widely expressed in many tissues where it may subserve signaling and other functions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.