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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