PMID- 32509173
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 1943-8141 (Print)
IS  - 1943-8141 (Electronic)
IS  - 1943-8141 (Linking)
VI  - 12
IP  - 5
DP  - 2020
TI  - Role of MKP-5-p38/MAPK pathway in Clopidogrel-induced gastric mucosal epithelial 
      cells apoptosis and tight junction dysfunction.
PG  - 1741-1753
AB  - Bleeding and delayed healing of gastric ulcer are well-recognized in patients 
      following Clopidorgrel treatment. Our previous studies have shown that 
      endoplasmic reticulum stress (ER) is involved in Clopidogrel-induced gastric 
      mucosal damage through activating p38 mitogen-activated protein kinases (MAPK) 
      pathway. This present study aims to further investigate the role of MAP kinase 
      phosphatase 5 (MKP-5), a MKP known to dephosphorylate and inactivate p38/MAPK, in 
      Clopidogrel-induced gastric mucosal injury and the underlying mechanisms. It 
      shows that MKP-5 is down-regulated at both mRNA and protein levels in the gastric 
      mucosa from bleeding patients who took Clopidogrel over one year. In vitro study 
      using human gastric epithelial cell line GES-1 demonstrates that exposure to 
      Clopidorgrel (1.0-2.0 mM) increases phosphorylation of p38/MAPK and decreases 
      MKP-5 expression simultaneously. Overexpression of MKP-5 promotes GES-1 cell 
      proliferation and reduces apoptosis following Clopidogrel exposure. 
      Interestingly, overexpression of MKP-5 also attenuates Clopidorgrel-induced tight 
      junction (TJ) destruction by down-regulating expression of ER stress-related 
      protein C/EBP homologous protein (CHOP) and tribbles pseudokinase 3 (TRIB3). 
      These three effects, increased proliferation, reduced apoptosis and attenuated TJ 
      destruction, are regulated through inhibited phosphorylation of p38/MAPK 
      signaling pathway. We conclude that MKP-5 is down-regulated in 
      Clopidogrel-induced gastric mucosa injury in vivo and in vitro via 
      phosphorylation and activation of p38/MAPK signaling pathway. Overexpression of 
      MKP-5 reverses Clopidogrel-induced gastric mucosal injury. These findings imply 
      that MKP-5 may be a potential therapeutic target in Clopidogrel-induced gastric 
      mucosal injury and bleeding.
CI  - AJTR Copyright (c) 2020.
FAU - Wu, Hailu
AU  - Wu H
AD  - Medical School of Southeast University Nanjing 210009, People's Republic of 
      China.
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
FAU - Ming, Wei
AU  - Ming W
AD  - Medical School of Southeast University Nanjing 210009, People's Republic of 
      China.
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
FAU - Tan, Jiacheng
AU  - Tan J
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
FAU - Lu, Qin
AU  - Lu Q
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
FAU - Mulmi Shrestha, Sachin
AU  - Mulmi Shrestha S
AD  - Medical School of Southeast University Nanjing 210009, People's Republic of 
      China.
FAU - Li, Nan
AU  - Li N
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
FAU - Wu, Guoqiu
AU  - Wu G
AD  - Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University 
      Nanjing 210009, People's Republic of China.
FAU - Zhang, Zhenyu
AU  - Zhang Z
AD  - Division of Gastroenterology, Department of Medicine, Nanjing Medical University 
      Nanjing First Hospital Nanjing 210009, People's Republic of China.
FAU - Shi, Ruihua
AU  - Shi R
AD  - Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast 
      University Nanjing 210009, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20200515
PL  - United States
TA  - Am J Transl Res
JT  - American journal of translational research
JID - 101493030
PMC - PMC7269986
OTO - NOTNLM
OT  - Clopidogrel
OT  - MKP-5
OT  - apoptosis
OT  - gastric bleeding
OT  - p38/MAPK
COIS- None.
EDAT- 2020/06/09 06:00
MHDA- 2020/06/09 06:01
PMCR- 2020/05/15
CRDT- 2020/06/09 06:00
PHST- 2019/10/18 00:00 [received]
PHST- 2020/04/21 00:00 [accepted]
PHST- 2020/06/09 06:00 [entrez]
PHST- 2020/06/09 06:00 [pubmed]
PHST- 2020/06/09 06:01 [medline]
PHST- 2020/05/15 00:00 [pmc-release]
PST - epublish
SO  - Am J Transl Res. 2020 May 15;12(5):1741-1753. eCollection 2020.