Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects

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 551±30 g, comprising 3.2±0.2 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 (9.4±1.3 to 12.2±2.1, 17.6±2.6, and 26.1±4.2 μmol/L, respectively; P<0.001) and a reduction in flow-mediated dilatation (4.1±0.8 to 2.1±0.8, 0.3±0.8, and -0.7±0.8%, respectively; P<0.001) at 4 hours. Compared with usual meal, animal protein increased plasma homocysteine (9.6±0.8 to 11.2±0.9 μmol/L, P=0.005) and reduced flow-mediated dilatation (4.5±0.7% to 0.9±0.6%, P=0.003). 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.