Physiological Increments in Plasma Homocysteine Induce Vascular Endothelial Dysfunction in Normal Human Subjects

Abstract

Abstract-We hypothesized that physiological increments in plasma homocysteine after low-dose oral methionine or dietary animal protein induce vascular endothelial dysfunction and that there is a graded, inverse relationship between homocysteine concentration and endothelial function. We studied 18 healthy volunteers aged 18 to 59 years. Brachial artery flow-mediated and glyceryltrinitrate-induced dilatation were measured after 1) oral L-methionine (10, 25, and 100 mg/kg), 2) dietary animal protein (lean chicken 551Ϯ30 g, comprising 3.2Ϯ0.2 g methionine), and 3) methionine-free amino acid mix (100 mg/kg). Methionine (10, 25, and 100 mg/kg) induced a dose-related increase in homocysteine (9.4Ϯ1.3 to 12.2Ϯ2.1, 17.6Ϯ2.6, and 26.1Ϯ4.2 mol/L, respectively; PϽ0.001) and a reduction in flow-mediated dilatation (4.1Ϯ0.8 to 2.1Ϯ0.8, 0.3Ϯ0.8, and Ϫ0.7Ϯ0.8%, respectively; PϽ0.001) at 4 hours. Compared with usual meal, animal protein increased plasma homocysteine (9.6Ϯ0.8 to 11.2Ϯ0.9 mol/L, Pϭ0.005) and reduced flow-mediated dilatation (4.5Ϯ0.7% to 0.9Ϯ0.6%, Pϭ0.003). Methionine-free amino acid mix did not induce any changes. Glyceryltrinitrate-induced dilatation was unchanged throughout. In this study, small physiological increments in plasma homocysteine after low-dose methionine and dietary animal protein induced vascular endothelial dysfunction. We propose that protein intake-induced increments in plasma homocysteine may have deleterious effects on vascular function and contribute to the development and progression of atherosclerosis. (Arteriosclerosis and Thrombosis. 1999;19:2922

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.…”

“…We found that, as with folate deficiency (which may effectively alter methylation reactions and deoxyribonucleotide biosynthesis), methionine loading (which maintains an efficient transmethylation pathway) promotes the occurrence of an oxidant stress-mediated prethrombotic state that is correlated with total plasma homocysteine concentration (Durand et al, 1997a;Durand and Blache, 1996). Several studies report that by altering flow-mediated endothelium-dependent vasodilation (Bellamy et al, 1998;Chambers et al, 1999aChambers et al, , 1999bKanani et al, 1999;Ungvari et al, 1999;Woo et al, 1999) and by affecting the blood coagulation system (Constant et al, 1999;Nappo et al, 1999), methionine load-induced hyperhomocysteinemia favors the occurrence of vascular spasm and thrombosis, and that endothelial dysfunction can be prevented by an antioxidant treatment (Chambers et al, 1999a;Kanani et al, 1999). These findings suggest that impaired methylation reactions and/or protein synthesis may not be the main mechanisms underlying moderate hyperhomocysteinemia-induced vascular disease.…”

“…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 .…”

“…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 . Nevertheless, two placebo-controlled crossover studies demonstrated that 2 months of folate supplementation improves endothelial function in hyperhomocysteinemic subjects by decreasing homocysteine levels (Bellamy et al, 1999;Chambers et al, 1999aChambers et al, , 1999b. Accordingly, administration of folic acid in combination with vitamins B 6 and B 12 improved endothelial dysfunction subsequent to hyperhomocysteinemia induced by methionine loading in healthy humans (Chao et al, 1999a).…”

High dietary protein intake induces endothelial dysfunction in uninephrectomized rats

“…However, it is not clear whether hypertriglyceridemia directly enhances albuminuria, although the former was reported to be independently associated with the prevalence of albuminuria in a diabetes population (17). On the other hand, small physiological increments in plasma homocysteine induced by dietary protein intake were reported to reduce flow-mediated vasodilatation in the brachial arteries (18). A cross-sectional clinical study suggested that plasma homocysteine could be an intermediate factor in the relationship between endothelial dysfunction and renal function (19).…”