THE ATHEROGENIC EFFECT OF EXCESS METHIONINE INTAKE

Authors: TROEN, ARON - TUFTS-HNRCA; LUTGENS, ESTHER - UNIV OF MAASTRICHT; SMITH, DONALD - TUFTS-HNRCA; ROSENBERG, IRWIN - TUFTS-HNRCA; SELHUB, JACOB - TUFTS-HNRCA

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/3/2003
Publication Date: 12/9/2003
Citation: TROEN, A.M., LUTGENS, E., SMITH, D.E., ROSENBERG, I.H., SELHUB, J. THE ATHEROGENIC EFFECT OF EXCESS METHIONINE INTAKE. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES. 2003;100:15089-15094.

Interpretive Summary: Elevated blood homocysteine is common in people with vascular disease such as narrowing and hardening of the arteries, heart disease, thrombosis and stroke. It is not clear whether the rise in blood homocysteine is a result of the disease or whether homocysteine has toxic properties that cause the disease. Homocysteine is derived from the metabolism of the essential amino acid methionine, and blood homocysteine levels may rise when food methionine intake is high or when folate, vitamin b12 or vitamin b6 intake is low. Feeding animals methionine-rich and vitamin deficient diets to raise blood homocysteine has been shown to promote vascular damage, but it has been difficult to determine whether such damage is related to the high methionine intake or to high blood homocysteine. We fed mice that have a genetic tendency to develop vascular disease, with experimental diets designed to raise blood homocysteine without increasing methionine intake, or to increase methionine intake without raising blood homocysteine. Our results show that in this model of vascular disease, methionine-rich diets increased vascular damage independently of blood homocysteine, and conversely, that high blood homocysteine alone did not increase such damage. These results suggest that high dietary methionine intake may be an important factor in vascular disease.

Technical Abstract: Methionine is the precursor of homocysteine, a sulfur amino acid intermediate in the methylation and transsulfuration pathways. Elevated plasma homocysteine (hyperhomocysteinemia) is associated with occlusive vascular disease. Whether homocysteine per se or a coincident metabolic abnormality causes vascular disease is still an open question. Animals with genetic hyperhomocysteinemia have so far failed to display atheromatous lesions. However, when methionine rich diets are used to induce hyperhomocysteinemia, vascular pathology is often observed. Such studies have not distinguished the effects of excess dietary methionine from those of hyperhomocysteinemia. We fed ApoE-deficient mice with experimental 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 B-vitamin deficiency and hyperhomocysteinemia. Mice fed methionine-rich diets had significant atheromatous pathology in the aortic arch even with normal plasma homocysteine levels, whereas mice fed B-vitamin deficient diets developed severe hyperhomocysteinemia without any increase in vascular pathology. Our findings suggest that moderate increases in methionine intake are atherogenic in susceptible mice. Although homocysteine may contribute to the effect of methionine, high plasma homocysteine was not independently atherogenic in this model. Some product of excess methionine metabolism rather than high plasma homocysteine per se may underlie the association of homocysteine with vascular disease.