1: Blood. 2003 May 15;101(10):3901-7. Epub 2002 Dec 27. 

Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase
and apolipoprotein E double knock-out mice with and without dietary
perturbation.

Wang H, Jiang X, Yang F, Gaubatz JW, Ma L, Magera MJ, Yang X, Berger PB, Durante
W, Pownall HJ, Schafer AI.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
hongw@bcm.tmc.edu

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
beta-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.

PMID: 12506016 [PubMed - indexed for MEDLINE]