Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice.

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 beta-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-alpha 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-6C(hi) and Ly-6C(mid) 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 micromol/L), but not l-cysteine, maintained the Ly-6C(hi) subset and induced the Ly-6C(mid) subset in cultured mouse primary splenocytes. Homocysteine-induced differentiation of the Ly-6C(mid) subset was prevented by catalase plus superoxide dismutase and the NAD(P)H oxidase inhibitor apocynin.

CONCLUSIONS:

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

• Authors: Daqing Zhang, Xiaohua Jiang, Pu Fang, Yan Yan, Jian Song, Sapna Gupta, Andrew I Schafer, William Durante, Warren D Kruger, Xiaofeng Yang, Hong Wang
• Journal: Circulation (Circulation) Vol. 120 Issue 19 Pg. 1893-902 (Nov 10 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19858416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• Ccl2 protein, mouse
• Chemokine CCL2
• Tumor Necrosis Factor-alpha
• Cystathionine beta-Synthase

Topics

• Animals
• Apolipoproteins E (genetics)
• Atherosclerosis (immunology, metabolism, pathology)
• Body Weight
• Cells, Cultured
• Chemokine CCL2 (blood)
• Cystathionine beta-Synthase (genetics, metabolism)
• Disease Models, Animal
• Female
• Homocystinuria (immunology, metabolism, pathology)
• Humans
• Hyperhomocysteinemia (immunology, metabolism, pathology)
• Macrophages (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocytes (immunology, pathology)
• Oxidative Stress (physiology)
• Pregnancy
• Severity of Illness Index
• Spleen (cytology)
• Tumor Necrosis Factor-alpha (blood)
• Vasculitis (immunology, metabolism, pathology)