Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1470-1476
doi: 10.1161/hq0901.096582
doi: 10.1161/hq0901.096582
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Dietary Supplementation With Methionine and Homocysteine Promotes Early Atherosclerosis but Not Plaque Rupture in ApoE-Deficient Mice
From the Departments of Cardiology (J.Z., E.F., J.B.) and Clinical Biochemistry (J.M.), and the Institute of Experimental Clinical Research (J.Z., H.B.R., E.F.), Aarhus University Hospital (Skejby), and the Department of Connective Tissue Biology, Institute of Anatomy (C.C.D.), Aarhus University, Aarhus, Denmark; and the Hamilton Civic Hospital Research Centre and McMaster University (R.C.A.), Hamilton, Canada.
Correspondence to Erling Falk, MD, PhD, Department of Cardiology (Research), Aarhus University Hospital (Skejby), DK-8200 Aarhus N, Denmark. E-mail erling.falk{at}iekf.au.dk
Abstract—— Hyperhomocysteinemia is an independent risk factor for atherothrombosis. However, causality is unproven, and it remains unknown whether hyperhomocysteinemia promotes atherosclerosis, plaque rupture, and/or thrombosis. We evaluated the short- and long-term effects of hyperhomocysteinemia on plaque size and structure in 99 atherosclerosis-prone apolipoprotein E-deficient mice. Hyperhomocysteinemia was induced by methionine (Met) or homocysteine (HcyH) supplementation: low Met (+11 g Met/kg food), high Met (+33 g Met/kg food), low HcyH (0.9 g HcyH/L drinking water), and high HcyH (1.8 g HcyH/L drinking water). Met and HcyH supplementation significantly raised plasma total homocysteine levels by 4- to 16-fold above those observed in mice fed a control diet (up to 146.1 µmol/L). Compared with controls, aortic root plaque size was significantly larger in supplemented groups after 3 months (56% and 173% larger in high-Met and high-HcyH, respectively) but not after 12 months. Hyperhomocysteinemia was associated with an increase in the amount 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 hyperhomocysteinemia. Many plaques in both control and supplemented mice appeared 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 plaque rupture.
Key Words: apoE-deficient mouse • homocysteine • atherosclerosis • plaque rupture
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