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Published on: October 17, 2017
Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and
Daqing Zhang1, Pu Fang, Xiaohua Jiang
1Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Insights
Hyperhomocysteinemia (HHcy) drives atherosclerosis by promoting inflammatory monocyte differentiation and macrophage maturation in vessel walls. Hcy-lowering therapy and antioxidants reversed these effects, indicating an oxidative stress mechanism.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Disorders
Background:
- Hyperhomocysteinemia (HHcy) is linked to accelerated atherosclerosis and increased inflammatory monocytes (MC).
- The direct role of HHcy in atherogenesis and its impact on vascular inflammation remain unclear.
- The underlying molecular mechanisms are not well understood.
Purpose of the Study:
- To investigate the causative role of HHcy in atherosclerosis development.
- To determine the effect of HHcy on inflammatory monocyte differentiation.
- To elucidate the mechanism by which HHcy influences vascular inflammation.
Main Methods:
- A novel mouse model with hyperhomocysteinemia and hyperlipidemia (Ldlr(-/-) Cbs(-/+)) was generated.
- High methionine diet induced severe HHcy; vitamin supplementation lowered plasma Hcy levels.
- Bone marrow transplantation traced cell origins; inflammatory monocyte differentiation and cytokine levels were analyzed.
Main Results:
- HHcy accelerated atherosclerosis and promoted Ly6C(high) inflammatory monocyte differentiation in both bone marrow and tissue-derived cells.
- Elevated plasma TNF-α, IL-6, and MCP-1, increased vessel wall monocyte accumulation, and enhanced macrophage maturation were observed.
- Hcy-lowering therapy, antioxidants, and folic acid reversed HHcy-induced atherosclerosis, inflammation, and oxidative stress.
Conclusions:
- HHcy directly causes vessel wall inflammatory monocyte differentiation and macrophage maturation, contributing to atherosclerosis.
- The mechanism involves oxidative stress, as evidenced by the reversal of effects by antioxidants and folic acid.
- These findings highlight HHcy as a significant risk factor for atherosclerosis mediated by inflammatory monocytes.
Rationale:
Hyperhomocysteinemia (HHcy) accelerates atherosclerosis and increases inflammatory monocytes (MC) in peripheral tissues. However, its causative role in atherosclerosis is not well established and its effect on vascular inflammation has not been studied. The underlying mechanism is unknown.
Objective:
This study examined the causative role of HHcy in atherogenesis and its effect on inflammatory MC differentiation.
Methods And Results:
We generated a novel HHcy and hyperlipidemia mouse model, in which cystathionine β-synthase (CBS) and low-density lipoprotein receptor (LDLr) genes were deficient (Ldlr(-/-) Cbs(-/+)). Severe HHcy (plasma homocysteine (Hcy)=275 μmol/L) was induced by a high methionine diet containing sufficient basal levels of B vitamins. Plasma Hcy levels were lowered to 46 μmol/L from 244 μmol/L by vitamin supplementation, which elevated plasma folate levels. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic mice after sublethal irradiation of the recipient. HHcy accelerated atherosclerosis and promoted Ly6C(high) inflammatory MC differentiation of both BM and tissue origins in the aortas and peripheral tissues. It also elevated plasma levels of TNF-α, IL-6, and MCP-1; increased vessel wall MC accumulation; and increased macrophage maturation. Hcy-lowering therapy reversed HHcy-induced lesion formation, plasma cytokine increase, and blood and vessel inflammatory MC (Ly6C(high+middle)) accumulation. Plasma Hcy levels were positively correlated with plasma levels of proinflammatory cytokines. In primary mouse splenocytes, L-Hcy promoted rIFNγ-induced inflammatory MC differentiation, as well as increased TNF-α, IL-6, and superoxide anion production in inflammatory MC subsets. Antioxidants and folic acid reversed L-Hcy-induced inflammatory MC differentiation and oxidative stress in inflammatory MC subsets.
Conclusions:
HHcy causes vessel wall inflammatory MC differentiation and macrophage maturation of both BM and tissue origins, leading to atherosclerosis via an oxidative stress-related mechanism.
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