PMID- 36399957
OWN - NLM
STAT- MEDLINE
DCOM- 20221210
LR  - 20221217
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 58
DP  - 2022 Dec
TI  - Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive 
      impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.
PG  - 102540
LID - S2213-2317(22)00312-3 [pii]
LID - 10.1016/j.redox.2022.102540 [doi]
LID - 102540
AB  - BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular 
      cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to 
      oxidative stress in vascular dysfunction. The aim of this study was designed to 
      examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related 
      post-translational modification of cysteine. METHODS: The VCI model was induced 
      by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The 
      cognitive functions were evaluated by step-down avoidance test, passive avoidance 
      step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation 
      was assayed using a biotin-switch method. RESULTS: In cell-free system, nitric 
      oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 
      activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced 
      tetrahydrobiopterin, and induced oxidative stress, which were attenuated by 
      N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to 
      alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL 
      incubation or iNOS overexpression promoted endothelial cellular senescence, but 
      abolished by exogenous expression of MT-GCH1 or pharmacological approaches 
      including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, 
      long-term administration of HTL induced GCH1 S-nitrosylation and vascular 
      stiffness, decreased cerebral blood flow, and damaged the cognitive functions. 
      However, these abnormalities induced by HTL administration were rescued by 
      enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 
      S-nitrosylation was increased and cognitive functions were impaired in patients 
      with HHcy. CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives 
      GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive 
      impairments.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Yin, Ya-Ling
AU  - Yin YL
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China.
FAU - Chen, Yuan
AU  - Chen Y
AD  - The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese 
      Ministry of Education, Chinese National Health Commission and Chinese Academy of 
      Medical Sciences, The State and Shandong Province Joint Key Laboratory of 
      Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 
      Jinan, Shandong, China.
FAU - Ren, Feng
AU  - Ren F
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China.
FAU - Wang, Lu
AU  - Wang L
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China.
FAU - Zhu, Mo-Li
AU  - Zhu ML
AD  - School of Pharmacy, Henan International Joint Laboratory of Cardiovascular 
      Remodeling and Drug Intervention, Xinxiang Medical University, Xinxiang, Henan, 
      China.
FAU - Lu, Jun-Xiu
AU  - Lu JX
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China; School of Pharmacy, Henan International Joint 
      Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Medical 
      University, Xinxiang, Henan, China.
FAU - Wang, Qian-Qian
AU  - Wang QQ
AD  - School of Pharmacy, Henan International Joint Laboratory of Cardiovascular 
      Remodeling and Drug Intervention, Xinxiang Medical University, Xinxiang, Henan, 
      China.
FAU - Lu, Cheng-Biao
AU  - Lu CB
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China.
FAU - Liu, Chao
AU  - Liu C
AD  - Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, 
      Hubei University of Science and Technology, Xianning, China.
FAU - Bai, Yong-Ping
AU  - Bai YP
AD  - School of Pharmacy, Henan International Joint Laboratory of Cardiovascular 
      Remodeling and Drug Intervention, Xinxiang Medical University, Xinxiang, Henan, 
      China; Department of Geriatric Medicine and Department of Cardiovascular 
      Medicine, Coronary Circulation Center, National Clinical Research Center for 
      Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 
      China.
FAU - Wang, Shuang-Xi
AU  - Wang SX
AD  - The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese 
      Ministry of Education, Chinese National Health Commission and Chinese Academy of 
      Medical Sciences, The State and Shandong Province Joint Key Laboratory of 
      Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 
      Jinan, Shandong, China; School of Pharmacy, Henan International Joint Laboratory 
      of Cardiovascular Remodeling and Drug Intervention, Xinxiang Medical University, 
      Xinxiang, Henan, China; Hubei Key Laboratory of Cardiovascular, Cerebrovascular, 
      and Metabolic Disorders, Hubei University of Science and Technology, Xianning, 
      China. Electronic address: shuangxiwang@sdu.edu.cn.
FAU - Wang, Jian-Zhi
AU  - Wang JZ
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of the Ministry of Education 
      of China for Neurological Disorders, Tongji Medical College, Huazhong University 
      of Science and Technology, Wuhan, Hubei, China. Electronic address: 
      wangjz@mail.hust.edu.cn.
FAU - Li, Peng
AU  - Li P
AD  - Sino-UK Joint Laboratory of Brain Function and Injury and Department of 
      Physiology and Neurobiology, School of Basic Medical Sciences, Xinxiang Medical 
      University, Xinxiang, China; School of Pharmacy, Henan International Joint 
      Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Medical 
      University, Xinxiang, Henan, China; Hubei Key Laboratory of Cardiovascular, 
      Cerebrovascular, and Metabolic Disorders, Hubei University of Science and 
      Technology, Xianning, China. Electronic address: pengli@xxmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221113
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - K848JZ4886 (Cysteine)
RN  - EC 3.5.4.16 (GTP Cyclohydrolase)
RN  - D5H88XF24X (homocysteine thiolactone)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 3.5.4.16 (Gch1 protein, mouse)
RN  - EC 3.5.4.16 (GCH1 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Cognitive Dysfunction/etiology/metabolism
MH  - Cysteine/metabolism
MH  - Endothelial Cells/metabolism
MH  - GTP Cyclohydrolase
MH  - *Hyperhomocysteinemia/chemically induced/metabolism
MH  - Nitric Oxide/metabolism
MH  - Nitrosative Stress
PMC - PMC9673109
OTO - NOTNLM
OT  - Endothelial cell
OT  - GTP cyclohydrolase 1
OT  - Nitrosative stress
OT  - S-nitrosylation
OT  - Vascular cognitive impairment
COIS- Declaration of competing interest We all authors stated that we have no conflicts 
      of interest.Ya-Ling Yin, Yuan Chen, Feng Ren, Lu Wang, Mo-Li Zhu, Jun-Xiu Lu, 
      Qian-Qian Wang, Cheng-Biao Lu, Chao Liu, Yong-Ying Bai, Shuang-Xi Wang, Jian-Zhi 
      WangPeng Li.
EDAT- 2022/11/19 06:00
MHDA- 2022/12/11 06:00
PMCR- 2022/11/13
CRDT- 2022/11/18 18:26
PHST- 2022/10/11 00:00 [received]
PHST- 2022/11/02 00:00 [revised]
PHST- 2022/11/11 00:00 [accepted]
PHST- 2022/11/19 06:00 [pubmed]
PHST- 2022/12/11 06:00 [medline]
PHST- 2022/11/18 18:26 [entrez]
PHST- 2022/11/13 00:00 [pmc-release]
AID - S2213-2317(22)00312-3 [pii]
AID - 102540 [pii]
AID - 10.1016/j.redox.2022.102540 [doi]
PST - ppublish
SO  - Redox Biol. 2022 Dec;58:102540. doi: 10.1016/j.redox.2022.102540. Epub 2022 Nov 
      13.