PMID- 30571174 OWN - NLM STAT- MEDLINE DCOM- 20190729 LR - 20200309 IS - 1524-4636 (Electronic) IS - 1079-5642 (Print) IS - 1079-5642 (Linking) VI - 38 IP - 12 DP - 2018 Dec TI - Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE(-/-) (Apolipoprotein E Deficient) Mice. PG - 2780-2792 LID - 10.1161/ATVBAHA.118.311806 [doi] AB - Objective- Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined. Approach and Results- ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADK(F/F)) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE(-/-) (apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the ABCG1 (ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation. Conclusions- Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE(-/-) mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases. FAU - Zhang, Min AU - Zhang M AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). FAU - Zeng, Xianqiu AU - Zeng X AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Yang, Qiuhua AU - Yang Q AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Xu, Jiean AU - Xu J AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Liu, Zhiping AU - Liu Z AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Zhou, Yaqi AU - Zhou Y AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Cao, Yapeng AU - Cao Y AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). FAU - Zhang, Xiaoyu AU - Zhang X AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). FAU - An, Xiaofei AU - An X AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). AD - Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China (X.A.). FAU - Xu, Yiming AU - Xu Y AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). AD - School of Basic Medical Sciences, Guangzhou Medical University, China (Y.X.). FAU - Huang, Lei AU - Huang L AD - Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, China (L.H., Z.H., T.W.). FAU - Han, Zhen AU - Han Z AD - Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, China (L.H., Z.H., T.W.). FAU - Wang, Tao AU - Wang T AD - Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, China (L.H., Z.H., T.W.). FAU - Wu, Chaodong AU - Wu C AD - Department of Nutrition and Food Science, Texas A&M University, College Station, TX (C.W.). FAU - Fulton, David J AU - Fulton DJ AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Weintraub, Neal L AU - Weintraub NL AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). FAU - Hong, Mei AU - Hong M AD - From the Key Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, Drug Discovery Center, Peking University Shenzhen Graduate School, China (M.Z., X.Z., Q.Y., J.X., Z.L., Y.Z., Y.C., X.Z., M.H.). FAU - Huo, Yuqing AU - Huo Y AD - Vascular Biology Center, Medical College of Georgia, Augusta University, GA (X.Z., Q.Y., J.X., Z.L., Y.Z., X.A., Y.X., D.J.F., N.L.W., Y.H.). AD - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University (Y.H.). LA - eng GR - R01 DK095862/DK/NIDDK NIH HHS/United States GR - R01 HL126949/HL/NHLBI NIH HHS/United States GR - R01 HL142097/HL/NHLBI NIH HHS/United States GR - R01 HL134934/HL/NHLBI NIH HHS/United States GR - R01 AR070029/AR/NIAMS NIH HHS/United States GR - R01 HL095556/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (ABCG1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.1.20 (Adenosine Kinase) MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/*genetics/metabolism MH - Adenosine Kinase/*deficiency/genetics MH - Animals MH - Aorta/*enzymology/pathology MH - Aortic Diseases/enzymology/genetics/pathology/*prevention & control MH - Atherosclerosis/enzymology/genetics/pathology/*prevention & control MH - Cells, Cultured MH - Cholesterol/metabolism MH - DNA Methylation MH - Disease Models, Animal MH - *Epigenesis, Genetic MH - Female MH - Foam Cells/*enzymology/pathology MH - Male MH - Mice, Inbred C57BL MH - *Mice, Knockout, ApoE MH - Plaque, Atherosclerotic MH - Signal Transduction PMC - PMC6309817 MID - NIHMS1509069 OTO - NOTNLM OT - atherosclerosis OT - cholesterol efflux OT - foam cell OT - gene methylation EDAT- 2018/12/21 06:00 MHDA- 2019/07/30 06:00 PMCR- 2019/12/01 CRDT- 2018/12/21 06:00 PHST- 2018/12/21 06:00 [entrez] PHST- 2018/12/21 06:00 [pubmed] PHST- 2019/07/30 06:00 [medline] PHST- 2019/12/01 00:00 [pmc-release] AID - 10.1161/ATVBAHA.118.311806 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2018 Dec;38(12):2780-2792. doi: 10.1161/ATVBAHA.118.311806.