PMID- 29860106 OWN - NLM STAT- MEDLINE DCOM- 20181022 LR - 20210109 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 17 DP - 2018 Jul TI - GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation. PG - 386-399 LID - S2213-2317(18)30243-X [pii] LID - 10.1016/j.redox.2018.04.021 [doi] AB - The adaptive immune system plays a critical role in hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Recent studies suggest that HHcy aggravates atherosclerosis with elevated oxidative stress and reduced S-nitrosylation level of redox-sensitive protein residues in the vasculature. However, whether and how S-nitrosylation contributes to T-cell-driven atherosclerosis remain unclear. In the present study, we report that HHcy reduced the level of protein S-nitrosylation in T cells by inducing S-nitrosoglutathione reductase (GSNOR), the key denitrosylase that catalyzes S-nitrosoglutathione (GSNO), which is the main restored form of nitric oxide in vivo. Consequently, secretion of inflammatory cytokines [interferon-gamma (IFN-gamma) and interleukin-2] and proliferation of T cells were increased. GSNOR knockout or GSNO stimulation rectified HHcy-induced inflammatory cytokine secretion and T-cell proliferation. Site-directed mutagenesis of Akt at Cys224 revealed that S-nitrosylation at this site was pivotal for the reduced phosphorylation at Akt Ser473, which led to impaired Akt signaling. Furthermore, on HHcy challenge, as compared with GSNOR(+/+)ApoE(-/-) littermate controls, GSNOR(-/-)ApoE(-/-) double knockout mice showed reduced T-cell activation with concurrent reduction of atherosclerosis. Adoptive transfer of GSNOR(-/-) T cells to ApoE(-/-) mice fed homocysteine (Hcy) decreased atherosclerosis, with fewer infiltrated T cells and macrophages in plaques. In patients with HHcy and coronary artery disease, the level of plasma Hcy was positively correlated with Gsnor expression in peripheral blood mononuclear cells and IFN-gamma(+) T cells but inversely correlated with the S-nitrosylation level in T cells. These data reveal that T cells are activated, in part via GSNOR-dependent Akt denitrosylation during HHcy-induced atherosclerosis. Thus, suppression of GSNOR in T cells may reduce the risk of atherosclerosis. CI - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Li, Jing AU - Li J AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Zhang, Yan AU - Zhang Y AD - Department of Cardiology, Peking University First Hospital, Beijing 100034, China. FAU - Zhang, Yuying AU - Zhang Y AD - National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. FAU - Lu, Silin AU - Lu S AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Miao, Yutong AU - Miao Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Yang, Juan AU - Yang J AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Huang, Shenming AU - Huang S AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Ma, Xiaolong AU - Ma X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Han, Lulu AU - Han L AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Deng, Jiacheng AU - Deng J AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Fan, Fangfang AU - Fan F AD - Department of Cardiology, Peking University First Hospital, Beijing 100034, China. FAU - Liu, Bo AU - Liu B AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. FAU - Huo, Yong AU - Huo Y AD - Department of Cardiology, Peking University First Hospital, Beijing 100034, China. FAU - Xu, Qingbo AU - Xu Q AD - Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, UK. FAU - Chen, Chang AU - Chen C AD - National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China. Electronic address: changchen@moon.ibp.ac.cn. FAU - Wang, Xian AU - Wang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. Electronic address: xwang@bjmu.edu.cn. FAU - Feng, Juan AU - Feng J AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, 38 Xueyuan Road, Beijing 100191, China. Electronic address: juanfeng@bjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180501 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Apolipoproteins E) RN - 31C4KY9ESH (Nitric Oxide) RN - 57564-91-7 (S-Nitrosoglutathione) RN - 82115-62-6 (Interferon-gamma) RN - EC 1.2.- (Aldehyde Oxidoreductases) RN - EC 1.2.1.46 (formaldehyde dehydrogenase, glutathione-independent) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Adaptive Immunity/genetics MH - Aged MH - Aldehyde Oxidoreductases/*genetics MH - Animals MH - Apolipoproteins E/*genetics MH - Atherosclerosis/*genetics/metabolism/pathology MH - Female MH - Humans MH - Hyperhomocysteinemia/*genetics/metabolism/pathology MH - Interferon-gamma/genetics MH - Macrophages/metabolism/pathology MH - Male MH - Mice MH - Mice, Knockout MH - Middle Aged MH - Nitric Oxide/metabolism MH - Oxidation-Reduction MH - Oxidative Stress/genetics MH - Phosphorylation/genetics MH - Proto-Oncogene Proteins c-akt/*genetics MH - S-Nitrosoglutathione/metabolism MH - T-Lymphocytes/immunology/metabolism PMC - PMC6007174 OTO - NOTNLM OT - Akt OT - Atherosclerosis OT - GSNOR OT - Hyperhomocysteinemia OT - Medical Biology OT - Oxidoreductase OT - Post-Translational Modification OT - T cell EDAT- 2018/06/04 06:00 MHDA- 2018/10/23 06:00 PMCR- 2018/05/01 CRDT- 2018/06/04 06:00 PHST- 2018/04/01 00:00 [received] PHST- 2018/04/24 00:00 [revised] PHST- 2018/04/28 00:00 [accepted] PHST- 2018/06/04 06:00 [pubmed] PHST- 2018/10/23 06:00 [medline] PHST- 2018/06/04 06:00 [entrez] PHST- 2018/05/01 00:00 [pmc-release] AID - S2213-2317(18)30243-X [pii] AID - 10.1016/j.redox.2018.04.021 [doi] PST - ppublish SO - Redox Biol. 2018 Jul;17:386-399. doi: 10.1016/j.redox.2018.04.021. Epub 2018 May 1.