GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation
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, w...
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Format: | Article |
Language: | English |
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Elsevier
2018-07-01
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Series: | Redox Biology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171830243X |
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doaj-3622d2fd86ee41fd8f3da00c596a092d |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jing Li Yan Zhang Yuying Zhang Silin Lü Yutong Miao Juan Yang Shenming Huang Xiaolong Ma Lulu Han Jiacheng Deng Fangfang Fan Bo Liu Yong Huo Qingbo Xu Chang Chen Xian Wang Juan Feng |
spellingShingle |
Jing Li Yan Zhang Yuying Zhang Silin Lü Yutong Miao Juan Yang Shenming Huang Xiaolong Ma Lulu Han Jiacheng Deng Fangfang Fan Bo Liu Yong Huo Qingbo Xu Chang Chen Xian Wang Juan Feng GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation Redox Biology |
author_facet |
Jing Li Yan Zhang Yuying Zhang Silin Lü Yutong Miao Juan Yang Shenming Huang Xiaolong Ma Lulu Han Jiacheng Deng Fangfang Fan Bo Liu Yong Huo Qingbo Xu Chang Chen Xian Wang Juan Feng |
author_sort |
Jing Li |
title |
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation |
title_short |
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation |
title_full |
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation |
title_fullStr |
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation |
title_full_unstemmed |
GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation |
title_sort |
gsnor modulates hyperhomocysteinemia-induced t cell activation and atherosclerosis by switching akt s-nitrosylation to phosphorylation |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2018-07-01 |
description |
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-γ (IFN-γ) 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-γ+ 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. Taxonomy: Post-Translational Modification, Medical Biology, Oxidoreductase, Keywords: Hyperhomocysteinemia, Atherosclerosis, GSNOR, T cell, Akt |
url |
http://www.sciencedirect.com/science/article/pii/S221323171830243X |
work_keys_str_mv |
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doaj-3622d2fd86ee41fd8f3da00c596a092d2020-11-24T21:44:14ZengElsevierRedox Biology2213-23172018-07-0117386399GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylationJing Li0Yan Zhang1Yuying Zhang2Silin Lü3Yutong Miao4Juan Yang5Shenming Huang6Xiaolong Ma7Lulu Han8Jiacheng Deng9Fangfang Fan10Bo Liu11Yong Huo12Qingbo Xu13Chang Chen14Xian Wang15Juan Feng16Department 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, ChinaDepartment of Cardiology, Peking University First Hospital, Beijing 100034, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment 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, ChinaDepartment of Cardiology, Peking University First Hospital, Beijing 100034, ChinaDepartment 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, ChinaDepartment of Cardiology, Peking University First Hospital, Beijing 100034, ChinaCardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, UKNational 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; Corresponding authors.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; Corresponding authors.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; Corresponding authors.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-γ (IFN-γ) 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-γ+ 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. Taxonomy: Post-Translational Modification, Medical Biology, Oxidoreductase, Keywords: Hyperhomocysteinemia, Atherosclerosis, GSNOR, T cell, Akthttp://www.sciencedirect.com/science/article/pii/S221323171830243X |