title: Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis.
abstract: Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Pu
authors.initials: P
authors.lastname: Fang
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Daqing
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang, Liaoning, P.R. China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX.
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Surgery, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Choi
authors.affiliation: Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang, Liaoning, P.R. China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Han
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA Cardiovascular Research Center, School of Medicine, Temple University, Philadelphia, PA Sol Sherry Thrombosis Research Center, School of Medicine, Temple University, Philadelphia, PA.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
authors.affiliation: Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA Cardiovascular Research Center, School of Medicine, Temple University, Philadelphia, PA Sol Sherry Thrombosis Research Center, School of Medicine, Temple University, Philadelphia, PA hong.wang@temple.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D003541:Cystathionine beta-Synthase / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000276:immunology*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*
chemical_list: D001057:Apolipoproteins E; D003541:Cystathionine beta-Synthase