Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans

Abstract

Background-Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. Methods and Results-Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (Ϸ25 mol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477Ϯ82%; placebo, 673Ϯ110%; Pϭ0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3Ϯ2.7%) compared with placebo (8.2Ϯ1.6%, Pϭ0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (Pϭ0.03). Conclusions-Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension.Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

Reduction in plasma total homocysteine through increasing folate intake in healthy individuals is not associated with changes in measures of antioxidant activity or oxidant damage

“…The modest nature of the increase in plasma antoxidant activity associated with homocysteinelowering may reflect the relatively low plasma mean tHcy concentration in the cohort at baseline. It has been argued that an impaired endothelial function associated with transient elevation in plasma tHcy is mediated by oxidative mechanisms (Kanani et al, 1999;Chambers et al, 1999). The fall in plasma tHcy in response to folate intervention in the study reported here, did not elicit any improvement in endothelial function (to be reported elsewhere) which is consistent with the failure to observe any convincing effects of homocysteine-lowering on antioxidant activity or oxidative damage.…”

Impaired Homocysteine Metabolism and Atherothrombotic Disease

“…Furthermore, our own work, together with that of others, emphasizes that a moderate elevation of circulating homocysteine related to impaired homocysteine metabolism (resulting from folate deficiency or dietary methionine excess) might trigger vascular disorders by promoting vascular spasm and thrombosis (Bellamy et al, 1998;Chambers et al, 1999aChambers et al, , 1999bDurand et al, 1996bDurand et al, , 1997aKanani et al, 1999;Lentz et al, 1996;Nappo et al, 1999;Ungvari et al, 1999). Although the molecular role that reduced homocysteine plays in vascular disorders is unclear, experimental evidence indicates that the association between moderately elevated homocysteine levels and atherothrombotic disease is likely to be causal.…”

“…Moreover, the decreased thrombomodulin-dependent activation of protein C observed in hyperhomocysteinemic primates suggests that a moderate increase in circulating homocysteine alters endothelial antithrombotic properties (Lentz et al, 1996). Furthermore, recent studies in both laboratory animals and humans increasingly suggest that moderate hyperhomocysteinemia impairs endothelial-dependent vasodilation (Bellamy et al, 1999;Chambers et al, 1999aChambers et al, , 1999bKanani et al, 1999;Nappo et al, 1999;Ungvari et al, 1999;Woo et al, 1999). Despite normalization of plasma homocysteine concentration, administration of folic acid, vitamin B 6 , and vitamin B 12 for 6 months was insufficient to restore normal vascular function in monkeys maintained for 17 months on an atherosclerotic diet that produced both hypercholesterolemia and hyperhomocysteinemia .…”

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…41 It is likely, therefore, that HHcy decreases nitric oxide bioavailability through alternative mechanisms, such as accelerated oxidative inactivation of nitric oxide. 40 Homocysteine-induced oxidative inactivation of nitric oxide has been observed in vitro in cultured endothelial cells, 42 and evidence for increased oxidative inactivation of nitric oxide during HHcy has been obtained in animals using both pharmacological 41,[43][44][45][46] and genetic 47,48 approaches. Several types of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and peroxynitrite, may contribute to the oxidative inactivation of endothelium-derived nitric oxide in HHcy.…”