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 (↑Hcy) or l-homocystine (↑Hcy–Hcy), or diet high in l-methionine (↑Met), or diet high in B-vitamins (↑vitamin), or diets deficient in folate (↓folate) or vitamin B6 (↓B6). 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 ↑vitamin, ↓folate, ↓B6 and control groups (9.2–10.1 μmol/l, NS), but elevated mildly in the ↑Hcy–Hcy group (16.1 μmol/l) and moderately in the ↑Met and ↑Hcy groups (53.6 and 51.5 μmol/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.


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