Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in apoE-deficient mice

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.