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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
Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis
Diabetes. 2014 Dec;63(12) :4275-90
PMID: 25008174    PMCID: PMC4237991    URL: https://www.ncbi.nlm.nih.gov/pubmed/25008174
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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 beta-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 (MOs) and further increased inflammatory MC and MO levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MO 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 MO differentiation, at least in part, via DNA hypomethylation.
Fang, Pu Zhang, Daqing Cheng, Zhongjian Yan, Chenghui Jiang, Xiaohua Kruger, Warren D Meng, Shu Arning, Erland Bottiglieri, Teodoro Choi, Eric T Han, Yaling Yang, Xiao-Feng Wang, Hong eng R01 HL108910/HL/NHLBI NIH HHS/ R01 HL077288/HL/NHLBI NIH HHS/ R01 GM098772/GM/NIGMS NIH HHS/ HL108910/HL/NHLBI NIH HHS/ HL117654/HL/NHLBI NIH HHS/ R01 HL117654/HL/NHLBI NIH HHS/ R01 DK101404/DK/NIDDK NIH HHS/ R01 HL110764/HL/NHLBI NIH HHS/ HL110764/HL/NHLBI NIH HHS/ HL116917/HL/NHLBI NIH HHS/ HL077288/HL/NHLBI NIH HHS/ R01 HL116917/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Diabetes. 2014 Dec;63(12):4275-90. doi: 10.2337/db14-0809. Epub 2014 Jul 9.