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Publication
Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte
differentiation and atherosclerosis.
Authors Fang P, Zhang D, Cheng Z, Yan C, Jiang X, Kruger WD, Meng S, Arning E,
Bottiglieri T, Choi ET, Han Y, Yang XF, Wang H
Submitted By Submitted Externally on 8/14/2017
Status Published
Journal Diabetes
Year 2014
Date Published 12/1/2014
Volume : Pages 63 : 4275 - 90
PubMed Reference 25008174
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 ß-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.




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