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

We hypothesized that physiological increments in plasma homocysteine after low-dose oral methionine or dietary animal protein induce vascular endothel ial dysfunction and that there is a graded, inverse relationship between ho mocysteine concentration and endothelial function. We studied 18 healthy vo lunteers aged 18 to 59 years. Brachial artery flow-mediated and glyceryltri nitrate-induced dilatation were measured after 1) oral L-methionine (10, 25 , and 100 mg/kg), 2) dietary animal protein (lean chicken 551+/-30 g, compr ising 3.2+/-0.2 g methionine), and 3) methionine-free amino acid mix (100 m g/kg). Methionine (10, 25, and 100 mg/kg) induced a dose-related increase i n homocysteine (9.3+/-1.3 to 12.2+/-2.1, 17.6+/-2.6, and 26.1+/-4.2 mu mol/ 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 homocyste ine (9.6+/-0.8 to 11.2+/-0.9 mu mol/L, P=0.005) and reduced flow-mediated d ilatation (4.5+/-0.7% to 0.9+/-0.6%, P=0.003). Methionine-free amino acid m ix did not induce any changes. Glyceryltrinitrate-induced dilatation was un changed 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 h omocysteine may have deleterious effects on vascular function and contribut e to the development and progression of atherosclerosis.