PMID- 36674690
OWN - NLM
STAT- MEDLINE
DCOM- 20230124
LR  - 20230201
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 2
DP  - 2023 Jan 7
TI  - The Involvement of Cx43 in JNK1/2-Mediated Endothelial Mechanotransduction and 
      Human Plaque Progression.
LID - 10.3390/ijms24021174 [doi]
LID - 1174
AB  - Atherosclerotic lesions preferentially develop at bifurcations, characterized by 
      non-uniform shear stress (SS). The aim of this study was to investigate 
      SS-induced endothelial activation, focusing on stress-regulated mitogen-activated 
      protein kinases (MAPK) and downstream signaling, and its relation to gap junction 
      proteins, Connexins (Cxs). Human umbilical vein endothelial cells were exposed to 
      flow ("mechanical stimulation") and stimulated with TNF-alpha ("inflammatory 
      stimulation"). Phosphorylated levels of MAPKs (c-Jun N-terminal kinase (JNK1/2), 
      extracellular signal-regulated kinase (ERK), and p38 kinase (p38K)) were 
      quantified by flow cytometry, showing the activation of JNK1/2 and ERK. THP-1 
      cell adhesion under non-uniform SS was suppressed by the inhibition of JNK1/2, 
      not of ERK. Immunofluorescence staining and quantitative real-time PCR 
      demonstrated an induction of c-Jun and c-Fos and of Cx43 in endothelial cells by 
      non-uniform SS, and the latter was abolished by JNK1/2 inhibition. Furthermore, 
      plaque inflammation was analyzed in human carotid plaques (n = 40) using 
      immunohistochemistry and quanti-gene RNA-assays, revealing elevated Cx43(+) cell 
      counts in vulnerable compared to stable plaques. Cx43(+) cell burden in the 
      plaque shoulder correlated with intraplaque neovascularization and lipid core 
      size, while an inverse correlation was observed with fibrous cap thickness. Our 
      results constitute the first report that JNK1/2 mediates Cx43 mechanoinduction in 
      endothelial cells by atheroprone shear stress and that Cx43 is expressed in human 
      carotid plaques. The correlation of Cx43(+) cell counts with markers of plaque 
      vulnerability implies its contribution to plaque progression.
FAU - Tauchi, Miyuki
AU  - Tauchi M
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
AD  - Cognitive and Molecular Research Institute of Brain Diseases, Kurume University, 
      Kurume 830-0011, Japan.
FAU - Oshita, Kensuke
AU  - Oshita K
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
AD  - Department of Anesthesiology, School of Medicine, Kurume University, Kurume 
      830-0011, Japan.
FAU - Urschel, Katharina
AU  - Urschel K
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
FAU - Furtmair, Roman
AU  - Furtmair R
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
FAU - Kuhn, Constanze
AU  - Kuhn C
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
FAU - Stumpfe, Florian M
AU  - Stumpfe FM
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
FAU - Botos, Balazs
AU  - Botos B
AD  - Department of Vascular Surgery, Hospital of Nurnberg-Sud, 90471 Nurnberg, 
      Germany.
FAU - Achenbach, Stephan
AU  - Achenbach S
AUID- ORCID: 0000-0002-7596-095X
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
FAU - Dietel, Barbara
AU  - Dietel B
AD  - Department of Cardiology and Angiology, Erlangen University Hospital, 
      Friedrich-Alexander University Erlangen-Nurnberg (FAU), 91054 Erlangen, Germany.
LA  - eng
GR  - F/38/20/German Heart Research Foundation/
GR  - Hans und Gertie Fischer Stiftung/
PT  - Journal Article
DEP - 20230107
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Connexin 43)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - 0 (Connexins)
SB  - IM
MH  - Humans
MH  - *Connexin 43/genetics/metabolism
MH  - Mechanotransduction, Cellular
MH  - Cells, Cultured
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - *Plaque, Atherosclerotic/metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Connexins/metabolism
PMC - PMC9863493
OTO - NOTNLM
OT  - MAPK
OT  - atherogenesis
OT  - endothelial dysfunction
OT  - gap junctions
OT  - mechanotransduction
OT  - shear stress
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2023/01/22 06:00
MHDA- 2023/01/25 06:00
PMCR- 2023/01/07
CRDT- 2023/01/21 01:25
PHST- 2022/12/01 00:00 [received]
PHST- 2022/12/23 00:00 [revised]
PHST- 2022/12/31 00:00 [accepted]
PHST- 2023/01/21 01:25 [entrez]
PHST- 2023/01/22 06:00 [pubmed]
PHST- 2023/01/25 06:00 [medline]
PHST- 2023/01/07 00:00 [pmc-release]
AID - ijms24021174 [pii]
AID - ijms-24-01174 [pii]
AID - 10.3390/ijms24021174 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Jan 7;24(2):1174. doi: 10.3390/ijms24021174.