title: Sulfur amino acids and atherosclerosis: a role for excess dietary methionine.
abstract: The homocysteine theory of arteriosclerosis received credence when it was shown that after a methionine load, circulating homocysteine-cysteine concentrations were higher in cardiovascular disease patients than in healthy controls. Subsequent studies showing associations between homocysteine and coronary artery disease, stroke and cognitive impairment, relied on small increases in homocysteine concentration unlike the very high homocysteine seen in the rare genetic disorders that lead to homocystinuria and much higher homocysteine levels. Subsequent studies in cell culture, animals, and humans showed that a variety of cardiovascular adverse effects of "high homocysteine" introduced either as a nonphysiological bolus or as a methionine load led to high homocysteine. We fed apolipoprotein E-deficient mice diets designed to achieve three conditions: (1) high methionine intake with normal blood homocysteine, (2) high methionine intake with B vitamin deficiency and hyperhomocysteinemia, and (3) normal methionine intake with both B vitamin deficiency and hyperhomocysteinemia. We found that the mice fed methionine-rich diets had significant atheromatous pathology in the aortic arch even with normal plasma homocysteine levels. Mice fed B vitamin-deficient diets developed severe hyperhomocysteinemia but without any increase in vascular pathology. Our findings suggest that even moderate increases in methionine intake are atherogenic in susceptible mice while high plasma homocysteine is not.
authors.affiliation: Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.affiliation: Nutrition and Brain Health Laboratory, The Institute of Biochemistry Food and Nutrition Science, The Robert H. Smith Faculty of Agriculture Food and the Environment, The Hebrew University of Jerusalem, Israel.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Troen
mesh_terms: D000603:Amino Acids, Sulfur / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D001774:Blood Chemical Analysis; D004032:Diet; D004195:Disease Models, Animal; D006710:Homocysteine / Q000097:blood / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000097:blood / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology; D013997:Time Factors
chemical_list: D000603:Amino Acids, Sulfur; D001057:Apolipoproteins E; D015415:Biomarkers; D006710:Homocysteine; D008715:Methionine
keywords: ApoE deficiency; atherogenic; folate; homocysteuine; methionine