PMID- 36652042
OWN - NLM
STAT- MEDLINE
DCOM- 20240517
LR  - 20240517
IS  - 1573-7241 (Electronic)
IS  - 0920-3206 (Linking)
VI  - 38
IP  - 3
DP  - 2024 Jun
TI  - Mitogen-Activated Protein Kinases Mediate Adventitial Fibroblast Activation and 
      Neointima Formation via GATA4/Cyclin D1 Axis.
PG  - 527-538
LID - 10.1007/s10557-023-07428-1 [doi]
AB  - PURPOSE: Activation of mitogen-activated protein kinases (MAPKs) by pathological 
      stimuli participates in cardiovascular diseases. Dysfunction of adventitial 
      fibroblast has emerged as a critical regulator in vascular remodeling, while the 
      potential mechanism remains unclear. In this study, we sought to determine the 
      effect of different activation of MAPKs in adventitial fibroblast contributing to 
      neointima formation. METHODS: Balloon injury procedure was performed in male 
      12-week-old Sprague-Dawley rats. After injury, MAPK inhibitors were applied to 
      the adventitia of injured arteries to suppress MAPK activation. Adventitial 
      fibroblasts were stimulated by platelet-derived growth factor-BB (PDGF-BB) with 
      or without MAPK inhibitors. RNA sequencing was performed to investigate the 
      change of pathway and cell function. Wound healing, transwell assay, and flow 
      cytometry were used to analyze adventitial fibroblast function. RESULTS: 
      Phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular 
      regulated kinases 1/2 (ERK1/2) was increased in injured arteries after balloon 
      injury. In primary culture of adventitial fibroblasts, PDGF-BB increased 
      phosphorylation of p38, JNK, ERK1/2, and extracellular regulated kinase 5 (ERK5) 
      in a short time, which was normalized by their inhibitors respectively. Compared 
      with the injury group, perivascular administration of four MAPK inhibitors 
      significantly attenuated neointima formation by quantitative analysis of 
      neointimal area, intima to media (I/M) ratio, and lumen area. RNA sequencing of 
      adventitial fibroblasts treated with PDGF-BB with or without four inhibitors 
      demonstrated differentially expressed genes involved in multiple biological 
      processes, including cell adhesion, proliferation, migration, and inflammatory 
      response. Wound healing and transwell assays showed that four inhibitors 
      suppressed PDGF-BB-induced adventitial fibroblast migration. Cell cycle analysis 
      by flow cytometry demonstrated that JNK, ERK1/2, and ERK5 but not p38 inhibitor 
      blocked PDGF-BB-induced G1 phase release associated with decrease expression of 
      cell cycle protein Cyclin D1 and transcription factor GATA4. Moreover, four 
      inhibitors decreased macrophage infiltration into adventitia and monocyte 
      chemoattractant protein-1 (MCP-1) expression. CONCLUSION: These results suggest 
      that MAPKs differentially regulate activation of adventitial fibroblast through 
      GATA4/Cyclin D1 axis that participates in neointima formation.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Chen, Jing
AU  - Chen J
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Wei, Jin-Qiu
AU  - Wei JQ
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Hong, Mo-Na
AU  - Hong MN
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Zhang, Zhong
AU  - Zhang Z
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Zhou, Han-Dan
AU  - Zhou HD
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Lu, Yuan-Yuan
AU  - Lu YY
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Zhang, Jia
AU  - Zhang J
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Guo, Yue-Tong
AU  - Guo YT
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Chen, Xin
AU  - Chen X
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Wang, Ji-Guang
AU  - Wang JG
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Gao, Ping-Jin
AU  - Gao PJ
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
FAU - Li, Xiao-Dong
AU  - Li XD
AUID- ORCID: 0000-0002-3771-6286
AD  - Department of Cardiovascular Medicine, Department of Hypertension, Ruijin 
      Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of 
      Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University 
      School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China. flylxd@163.com.
LA  - eng
GR  - 81400191/National Natural Science Foundation of China/
GR  - 81900440/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20230118
PL  - United States
TA  - Cardiovasc Drugs Ther
JT  - Cardiovascular drugs and therapy
JID - 8712220
SB  - IM
MH  - Animals
MH  - *Neointima
MH  - *Rats, Sprague-Dawley
MH  - *Fibroblasts/drug effects/pathology/metabolism/enzymology
MH  - Male
MH  - *Adventitia/pathology/drug effects/metabolism/enzymology
MH  - *Mitogen-Activated Protein Kinases/metabolism
MH  - *Becaplermin/pharmacology
MH  - Cells, Cultured
MH  - *Cyclin D1/metabolism/genetics
MH  - Carotid Artery Injuries/pathology/enzymology/drug therapy/metabolism
MH  - Cell Movement/drug effects
MH  - Phosphorylation
MH  - Disease Models, Animal
MH  - Cell Proliferation/drug effects
MH  - Rats
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Vascular System Injuries/pathology/enzymology/metabolism/drug therapy
MH  - Signal Transduction
MH  - Angioplasty, Balloon/adverse effects
OTO - NOTNLM
OT  - Adventitia
OT  - Cyclin D1
OT  - GATA4
OT  - Inflammation
OT  - MAPKs
OT  - Neointima formation
EDAT- 2023/01/19 06:00
MHDA- 2024/05/17 12:43
CRDT- 2023/01/18 11:23
PHST- 2023/01/09 00:00 [accepted]
PHST- 2024/05/17 12:43 [medline]
PHST- 2023/01/19 06:00 [pubmed]
PHST- 2023/01/18 11:23 [entrez]
AID - 10.1007/s10557-023-07428-1 [pii]
AID - 10.1007/s10557-023-07428-1 [doi]
PST - ppublish
SO  - Cardiovasc Drugs Ther. 2024 Jun;38(3):527-538. doi: 10.1007/s10557-023-07428-1. 
      Epub 2023 Jan 18.