Hyperhomocysteinemia Potentiates Hyperglycemia-induced Inflammatory Monocyte Differentiation and Atherosclerosis
- Pu Fang1,4,
- Daqing Zhang1,4,
- Zhongjian Cheng1,4,
- Chenghui Yan7,
- Xiaohua Jiang1,4,
- Warren D. Kruger6,
- Shu Meng1,4,
- Erland Arning8,
- Teodoro Bottiglieri8,
- Eric T. Choi1,5,
- Yaling Han7,
- Xiao-feng Yang1,2,3,4 and
- Hong Wang1,2,3,4⇑
- 1Centers for Metabolic Disease Research, Temple University , Philadelphia, PA 19140
- 2Cardiovascular Research, Temple University, Philadelphia, PA 19140
- 3Sol Sherry Thrombosis Research, Temple University , Philadelphia, PA 19140
- 4Department of Pharmacology, Temple University , Philadelphia, PA 19140
- 5School of Medicine, Surgery, Temple University , Philadelphia, PA 19140
- 6Fox Chase Cancer Center, Philadelphia, PA 19111
- 7Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang, LIAONING 110840, P. R. China
- 8Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, Texas 75226
- Corresponding author: Hong Wang, Email:
Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in hyperglycemia (HG) associated atherogenesis 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 cystathionine β-synthase (Cbs) deficient mice in which homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using zinc supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with ApoE-/- mice and feeding 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 MNC, 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 (SAM)/s-adenosylhomocysteine (SAH) 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.
- Received May 21, 2014.
- Accepted June 26, 2014.
- © 2014 by the American Diabetes Association.
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