Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis

Pu Fang, Daqing Zhang, Zhongjian Cheng, Chenghui Yan, Xiaohua Jiang, Warren D. Kruger, Shu Meng, Erland Arning, Teodoro Bottiglieri, Eric T. Choi, Yaling Han, Xiao Feng Yang, Hong Wang

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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 atherosclerosissusceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine b-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 in flammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.

Original languageEnglish (US)
Pages (from-to)4275-4290
Number of pages16
JournalDiabetes
Volume63
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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