Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice

It has been demonstrated that hyperhomocysteinemia (HHcy) accelerates atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. In this study, vitamin-defined chow diets were used to induce HHcy in apoE(-/-) mice in an attempt to identify possible pathogenic pathways. Six-week-old female apoE(-/-) mice were divided into seven groups: vitamin-defined purified chow diet alone (control), or same diet supplemented with either D,L-homocysteine (THcy) or L-homocystine (up arrowHcy-Hcy), or diet high in L-methionine (up arrowMet), or diet high in B-vitamins (up arrowvitamin), or diets deficient in folate (down arrowfolate) or vitamin B-6(down arrowB(6)). Eighteen weeks later, plasma total homocysteine (tHcy), lipids and atherosclerotic plaque burden (aortic root, aortic arch, and brachiocephalic trunk) were measured. tHcy levels were similar in the up arrowvitamin, down arrowfolate, down arrowB(6) and control groups (9.2 - 10.1 mumol/l, NS), but elevated mildly in the up arrowHcy-Hcy group (16.1 mumol/l) and moderately in the up arrowMet and up arrowHcy groups (53.6 and 51.5 mumol/l, respectively). Mice in the latter two groups had significantly more atherosclerosis in the aortic root. Although B vitamin-supplementation failed to lower tHcy levels, mice had less atherosclerosis in the aortic arch. In summary, dietary methionine and homocysteine, but not homocystine, enhanced the development of atherosclerosis. Supplementation with B vitamins appeared to confer homocysteine-independent protection against atherosclerosis. These results suggest that (1) there may be a threshold level below which homocysteine is not atherogenic; (2) the atherogenic effect of HHcy may be mediated via an intracellular pathway; and/or (3) the anti-atherogenic effect of B vitamins in normohomocysteinemic mice is independent of tHcy levels. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.