J. Zhou et al., Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in apoE-deficient mice, ART THROM V, 21(9), 2001, pp. 1470-1476
Hyperhomocysteinemia is an independent risk factor for atherothrombosis. Ho
wever, causality is unproven, and it remains unknown whether hyperhomocyste
inemia promotes atherosclerosis, plaque rupture, and/or thrombosis. We eval
uated the short- and long-term effects of hyperhomocysteinemia on plaque si
ze and structure in 99 atherosclerosis-prone apolipoprotein E-deficient mic
e. Hyperhomocysteinemia was induced by methionine (Met) or homocysteine (Hc
yH) supplementation: low Met (+11 g Met/kg food), high Met (+33 g Met/kg fo
od), low HcyH (0.9 g HcyH/L drinking water), and high HcyH (1.8 g HcyH/L dr
inking water). Met and HcyH supplementation significantly raised plasma tot
al homocysteine levels by 4- to 16-fold above those observed in mice fed a
control diet (up to 146.1 mu mol/L). Compared with controls, aortic root pl
aque size was significantly larger in supplemented groups after 3 months (5
6% and 173% larger in high-Met and high-HcyH, respectively) but not after 1
2 months. Hyperhomocysteinemia was associated with an increase in the amoun
t of collagen in plaques after both 3 and 12 months. Mechanical testing of
the tail tendons revealed no weakening of collagen after 12 months of hyper
homocysteinemia. Many plaques in both control and supplemented mice appeare
d rupture prone morphologically, but all aortic root plaques and all but 1
coronary plaque had an intact surface without rupture or thrombosis. Thus,
diet-induced hyperhomocysteinemia promotes early atherosclerosis and plaque
fibrosis but does not, even in the long term, weaken collagen or induce pl
aque rupture.