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Circulation

Year: 2009  |  Volume: 120  |  Issue: 19  |  Page No.: 1893 - 1902

Hyperhomocysteinemia Promotes Inflammatory Monocyte Generation and Accelerates Atherosclerosis in Transgenic Cystathionine {beta}-Synthase-Deficient Mice

D Zhang, X Jiang, P Fang, Y Yan, J Song, S Gupta, A. I Schafer, W Durante, W. D Kruger, X Yang and H. Wang

Abstract

Background— Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Monocytes display inflammatory and resident subsets and commit to specific functions in atherogenesis. In this study, we examined the hypothesis that HHcy modulates monocyte heterogeneity and leads to atherosclerosis.

Methods and Results— We established a novel atherosclerosis-susceptible mouse model with both severe HHcy and hypercholesterolemia in which the mouse cystathionine β-synthase (CBS) and apolipoprotein E (apoE) genes are deficient and an inducible human CBS transgene is introduced to circumvent the neonatal lethality of the CBS deficiency (Tg-hCBS apoE–/– Cbs–/– mice). Severe HHcy accelerated atherosclerosis and inflammatory monocyte/macrophage accumulation in lesions and increased plasma tumor necrosis factor- and monocyte chemoattractant protein-1 levels in Tg-hCBS apoE–/– Cbs–/– mice fed a high-fat diet. Furthermore, we characterized monocyte heterogeneity in Tg-hCBS apoE–/– Cbs–/– mice and another severe HHcy mouse model (Tg-S466L Cbs–/–) with a disease-relevant mutation (Tg-S466L) that lacks hyperlipidemia. HHcy increased monocyte population and selective expansion of inflammatory Ly-6Chi and Ly-6Cmid monocyte subsets in blood, spleen, and bone marrow of Tg-S466L Cbs–/– and Tg-hCBS apoE–/– Cbs–/– mice. These changes were exacerbated in Tg-S466L Cbs–/– mice with aging. Addition of l-homocysteine (100 to 500 µmol/L), but not l-cysteine, maintained the Ly-6Chi subset and induced the Ly-6Cmid subset in cultured mouse primary splenocytes. Homocysteine-induced differentiation of the Ly-6Cmid subset was prevented by catalase plus superoxide dismutase and the NAD(P)H oxidase inhibitor apocynin.

Conclusion— HHcy promotes differentiation of inflammatory monocyte subsets and their accumulation in atherosclerotic lesions via NAD(P)H oxidase–mediated oxidant stress.

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