PMID- 25008174 OWN - NLM STAT- MEDLINE DCOM- 20150116 LR - 20220223 IS - 1939-327X (Electronic) IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 63 IP - 12 DP - 2014 Dec TI - Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis. PG - 4275-90 LID - 10.2337/db14-0809 [doi] AB - 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. CI - (c) 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. FAU - Fang, Pu AU - Fang P AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA. FAU - Zhang, Daqing AU - Zhang D AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA. FAU - Cheng, Zhongjian AU - Cheng Z AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA. FAU - Yan, Chenghui AU - Yan C AD - Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang, Liaoning, P.R. China. FAU - Jiang, Xiaohua AU - Jiang X AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA. FAU - Kruger, Warren D AU - Kruger WD AD - Fox Chase Cancer Center, Philadelphia, PA. FAU - Meng, Shu AU - Meng S AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA. FAU - Arning, Erland AU - Arning E AD - Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX. FAU - Bottiglieri, Teodoro AU - Bottiglieri T AD - Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX. FAU - Choi, Eric T AU - Choi ET AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Surgery, School of Medicine, Temple University, Philadelphia, PA. FAU - Han, Yaling AU - Han Y AD - Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang, Liaoning, P.R. China. FAU - Yang, Xiao-Feng AU - Yang XF AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA Cardiovascular Research Center, School of Medicine, Temple University, Philadelphia, PA Sol Sherry Thrombosis Research Center, School of Medicine, Temple University, Philadelphia, PA. FAU - Wang, Hong AU - Wang H AD - Center for Metabolic Disease Research, School of Medicine, Temple University, Philadelphia, PA Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA Cardiovascular Research Center, School of Medicine, Temple University, Philadelphia, PA Sol Sherry Thrombosis Research Center, School of Medicine, Temple University, Philadelphia, PA hong.wang@temple.edu. LA - eng GR - R01 HL108910/HL/NHLBI NIH HHS/United States GR - HL108910/HL/NHLBI NIH HHS/United States GR - HL117654/HL/NHLBI NIH HHS/United States GR - R01 HL117654/HL/NHLBI NIH HHS/United States GR - R01 DK101404/DK/NIDDK NIH HHS/United States GR - R01 HL110764/HL/NHLBI NIH HHS/United States GR - HL110764/HL/NHLBI NIH HHS/United States GR - R01 HL116917/HL/NHLBI NIH HHS/United States GR - R01 HL077288/HL/NHLBI NIH HHS/United States GR - R01 GM098772/GM/NIGMS NIH HHS/United States GR - HL116917/HL/NHLBI NIH HHS/United States GR - HL077288/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140709 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Apolipoproteins E) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) SB - IM MH - Animals MH - Apolipoproteins E/genetics MH - Atherosclerosis/complications/*immunology MH - Cell Differentiation/*immunology MH - Cystathionine beta-Synthase/genetics MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Humans MH - Hyperglycemia/complications/*immunology MH - Hyperhomocysteinemia/complications/*immunology MH - Inflammation/immunology MH - Macrophages/*immunology MH - Mice MH - Mice, Transgenic MH - Monocytes/*immunology PMC - PMC4237991 EDAT- 2014/07/11 06:00 MHDA- 2015/01/17 06:00 PMCR- 2015/12/01 CRDT- 2014/07/11 06:00 PHST- 2014/07/11 06:00 [entrez] PHST- 2014/07/11 06:00 [pubmed] PHST- 2015/01/17 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - db14-0809 [pii] AID - 0809 [pii] AID - 10.2337/db14-0809 [doi] PST - ppublish SO - Diabetes. 2014 Dec;63(12):4275-90. doi: 10.2337/db14-0809. Epub 2014 Jul 9.