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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-08-2606.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3901-3907
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Hyperhomocysteinemia accelerates atherosclerosis in cystathionine
 -synthase and apolipoprotein E double knock-out mice with and
without dietary perturbation
Hong Wang,
XiaoHua Jiang,
Fan Yang,
John W. Gaubatz,
Lang Ma,
Mark J. Magera,
XiaoFeng Yang,
Peter B. Berger,
William Durante,
Henry J. Pownall, and
Andrew I. Schafer
From the Departments of Medicine, Pharmacology, and
Pathology, Baylor College of Medicine, Houston, TX; VA Medical Center,
Houston, TX; and Mayo Clinic, Rochester, MN.
Although hyperhomocysteinemia is an independent risk factor for
cardiovascular disease, a direct role for homocysteine (Hcy) in this
disease remains to be shown. Whereas diet-induced hyperhomocysteinemia promotes atherosclerosis in animal models, the effects of Hcy on
atherogenesis in the absence of dietary perturbations is not known. We
have generated double knock-out mice with targeted deletions of the
genes for apolipoprotein E (apoE) and cystathionine  -synthase (CBS),
which converts Hcy to cystathionine.
ApoE //CBS/ mice developed aortic
lesions even in the absence of dietary manipulation; lesion area and
lesion cholesteryl ester (CE) and triglyceride (TG) contents increased
with animal age and plasma Hcy levels. Plasma total cholesterol was
significantly increased, whereas high density lipoprotein (HDL)
cholesterol and TG concentrations of
apoE//CBS/ mice were decreased.
Cholesterol esterification and activities of enzymes catalyzing CE or
TG formation in the vessel wall and in peritoneal macrophages were not
changed by hyperhomocysteinemia. However, uptake of human acetyl-LDL,
but not native low density lipoprotein (LDL), by mouse peritoneal
macrophages was higher in the presence of hyperhomocysteinemia. These
results suggest that isolated hyperhomocysteinemia is atherogenic and
alters hepatic and macrophage lipoprotein metabolism, in part, by
enhancing uptake of modified LDL.
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