ArticleCirculation research2012
Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice.
Article in Circulation research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 1 of them a synthesis that pooled it.
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Who cites it
79 citing papers in PubMed, 1 synthesis or guideline pooled it, 121 citations in OpenAlex.
- Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer's disease.Alzheimer's research & therapy · 2023Pooled it
- Hyperhomocysteinaemia is an independent risk factor of abdominal aortic aneurysm in a Chinese Han population.Scientific reports · 2016Trial
- One-carbon metabolism and cardiovascular disease: Molecular mechanisms, genetic influences, and epigenetic regulation.Biochemistry and biophysics reports · 2026Review
- A new paradigm: 46 structural cell types function as environment-supporting innate immune cells, with endothelial and vascular smooth muscle cells as key prototypes.iNew medicine · 2026Article
- Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model.Journal of Alzheimer's disease : JAD · 2025Article
- Physiopathology of polycystic ovary syndrome in endocrinology, metabolism and inflammation.Journal of ovarian research · 2025Review
- Dietary methionine supplementation promotes mice hematopoiesis after irradiation.Military Medical Research · 2024Article
- Perspective: Pathological transdifferentiation-a novel therapeutic target for cardiovascular diseases and chronic inflammation.Frontiers in cardiovascular medicine · 2024Article
- Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.Redox biology · 2023Article
- Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways.JCI insight · 2023Article
- Innate immunity of vascular smooth muscle cells contributes to two-wave inflammation in atherosclerosis, twin-peak inflammation in aortic aneurysms and trans-differentiation potential into 25 cell types.Frontiers in immunology · 2023Article
- Atheroprotective mechanism by which folic acid regulates monocyte subsets and function through DNA methylation.Clinical epigenetics · 2022Article
- The double-edged role of hydrogen sulfide in the pathomechanism of multiple liver diseases.Frontiers in pharmacology · 2022Review
- Editorial: Endothelial cells as innate immune cells.Frontiers in immunology · 2022Article
- Editorial: Highlights for Cardiovascular Therapeutics in 2021 - Trained Immunity, Immunometabolism, Gender Differences of Cardiovascular Diseases, and Novel Targets of Cardiovascular Therapeutics.Frontiers in cardiovascular medicine · 2022Article
- 29 mJournal of immunology research · 2022Article
- TGFB3-AS1 promotes Hcy-induced inflammationof macrophages via inhibiting the maturityof miR-144 and upregulating Rap1a.Molecular therapy. Nucleic acids · 2021Article
- IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms.JCI insight · 2021Article
- Article
- Trained Immunity and Reactivity of Macrophages and Endothelial Cells.Arteriosclerosis, thrombosis, and vascular biology · 2021Review
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
rationaleHyperhomocysteinemia (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.
objectiveThis study examined the causative role of HHcy in atherogenesis and its effect on inflammatory MC differentiation. METHODS AND
resultsWe 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.
conclusionsHHcy 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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