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 (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.
Zhou
Ji
J
Department of Cardiology, Aarhus University Hospital (Skejby), Aarhus, Denmark. jzhou@thrombosis.hhscr.org
Møller
Jan
J
Ritskes-Hoitinga
Merel
M
Larsen
Mogen L
ML
Austin
Richard C
RC
Falk
Erling
E
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D016122:Brachiocephalic Trunk / Q000473:pathology; D004032:Diet; D019587:Dietary Supplements; D005260:Female; D006710:Homocysteine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications*; D008055:Lipids / Q000097:blood; D008715:Methionine / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014815:Vitamins / Q000494:pharmacology*
D001057:Apolipoproteins E; D008055:Lipids; D014815:Vitamins; D006710:Homocysteine; D008715:Methionine