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

Abstract

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. (Blood. 2003;101: 3901-3907)

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…Our finding that ER stress and NF-kB activation are increased in the atherosclerotic lesions of mice with diet-induced HHcy provides support for this concept. 62 A recent study by Wang et al 27 has also shown that genetic hyperhomocysteimia in a hyperlipidemic background accelerates atherosclerosis. Using compound apoE and CBS double knockout mice, atherosclerotic lesion area and lipid content increased with total plasma homocysteine concentrations, independent of diet.…”

“…[25][26][27][28] Transgenic mice deficient in CBS or MTHFR have also been used as animal models of HHcy. Homozygous CBS-deficient mice have total plasma homocysteine levels 40-fold greater than normal and suffer from severe growth retardation, hepatic steatosis, and dislocation of the lens 109 -phenotypic changes also observed in human patients with homocystinuria.…”

“…Several recent studies have demonstrated that mild HHcy accelerates atherogenesis in apoE-deficient mice. [25][26][27][28] Zhou et al 25,26 demonstrated that apoE-deficient mice fed chow diets supplemented with either methionine or homocysteine developed larger, more complex and more numerous arterial lesions, compared to mice fed control diets (Figure 3). Lesions were rich in smooth muscle cells and collagen, a result consistent with the ability of homocysteine to stimulate SMC proliferation and extracellular matrix deposition.…”

“…24 Furthermore, a direct causal relationship between induction of HHcy and accelerated atherosclerosis has been reported in apolipoprotein E (apoE)-deficient mice with diet-and/or genetic-induced HHcy. [25][26][27][28] Given that oral administration of folic acid or a combination of B vitamins can decrease HHcy and attenuate atherogenesis in these animal models, 26,28 there is growing interest for treatment of HHcy as a strategy for prevention of atherothrombotic disease.…”

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

“…Patient and animal studies have shown a positive correlation between increased homocysteine (Hcy) levels with increased risk for cardiovascular complications including endothelial dysfunction, atherosclerosis, and myocardial infarction [1][2][3]. In vitro studies have proven that Hcy causes proliferation of SMC [4,5], but also oxidative stress [6] and cell death in endothelial cells [7,8].…”