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 (upward arrow Hcy) or L-
homocystine (upward arrow Hcy-Hcy), or diet high in
L-methionine (upward arrow Met), or diet high in
B-vitamins (upward arrow
vitamin), or diets deficient in
folate (downward arrow
folate) or
vitamin B(6) ( downward arrow B(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 upward arrow
vitamin, downward arrow
folate, downward arrow B(6) and control groups (9.2-10.1 micromol/l, NS), but elevated mildly in the upward arrow Hcy-Hcy group (16.1 micromol/l) and moderately in the upward arrow Met and upward arrow Hcy groups (53.6 and 51.5 micromol/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.