PMID- 35485167
OWN - NLM
STAT- MEDLINE
DCOM- 20220502
LR  - 20220716
IS  - 2165-5987 (Electronic)
IS  - 2165-5979 (Print)
IS  - 2165-5979 (Linking)
VI  - 13
IP  - 4
DP  - 2022 Apr
TI  - MEK1/2 inhibitor inhibits neointima formation by activating miR-126-3p/ C-X-C 
      motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) axis.
PG  - 11214-11227
LID - 10.1080/21655979.2022.2063496 [doi]
AB  - Endothelial dysfunction is an initial and essential step in vascular-remodeling 
      diseases, including atherosclerosis and neointima formation. During vascular 
      remodeling, activated endothelial cells can release pro-inflammatory factors that 
      promote phenotypic switching of vascular smooth muscle cells (VSMCs) to the 
      proliferative phenotype. We previously reported that MEK1/2 inhibitor, U0126, has 
      a protective effect on the development of atherosclerosis and vascular 
      calcification. However, the effect of MEK1/2 inhibitors on neointimal formation 
      and the underlying mechanism is not fully understood. We determined that MEK1/2 
      inhibitor reduced carotid artery ligation-induced neointimal formation, while 
      increased collagen and elastin levels and vascular integrality. Mechanistically, 
      MEK1/2 inhibitor or ERK1/2 siRNA increased miR-126-3p level in endothelial cells, 
      thereby inhibiting expression of regular of G-protein signaling 16 (RGS16), a 
      miR-126-3p target gene, to activate the C-X-C motif chemokine ligand 12 
      (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signaling pathway. Accordingly, 
      miR-126-3p was also increased by U0126 in serum and carotid artery. RGS16 was 
      inhibited while CXCR4 and CXCL12 was increased by U0126 in neointimal areas, 
      especially in the endothelium. Moreover, similar results were observed in 
      atherosclerotic plaques of high-fat diet-fed apolipoprotein E deficiency 
      (apoE(-/-)) mice. In addition, vascular cell adhesion molecule 1 (VCAM-1), 
      another miR-126-3p target gene, was reduced by U0126 in the neointimal areas, 
      resulting reduced monocytes/macrophages accumulation. Taken together, our results 
      indicate that MEK1/2 inhibitor can reduce neointima formation by activating 
      endothelial miR-126-3p production to facilitate endothelium repair while reduce 
      monocyte adhesion/infiltration.
FAU - Yan, Yali
AU  - Yan Y
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Zhu, Mengmeng
AU  - Zhu M
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Ma, Jialing
AU  - Ma J
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - He, Xiaoyu
AU  - He X
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Yang, Xiaoxiao
AU  - Yang X
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Xu, Hongmei
AU  - Xu H
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Jiang, Meixiu
AU  - Jiang M
AD  - The Institute of Translational Medicine, the National Engineering Research Center 
      for Bioengineering Drugs and the Technologies, Nanchang University, Nanchang, 
      Jiangxi, China.
FAU - Zhang, Shuang
AU  - Zhang S
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Duan, Yajun
AU  - Duan Y
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
FAU - Han, Jihong
AU  - Han J
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
AD  - College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key 
      Laboratory of Bioactive Materials of Ministry of Education, Nankai University, 
      Tianjin, Hebei, China.
FAU - Chen, Yuanli
AU  - Chen Y
AUID- ORCID: 0000-0003-0813-3847
AD  - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher 
      Education Institutes, School of Food and Biological Engineering, Hefei University 
      of Technology, Hefei, Anhui, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Bioengineered
JT  - Bioengineered
JID - 101581063
RN  - 0 (CXCR4 protein, mouse)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcl12 protein, mouse)
RN  - 0 (Ligands)
RN  - 0 (MicroRNAs)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, CXCR4)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - *Atherosclerosis/genetics
MH  - Chemokine CXCL12/metabolism
MH  - Endothelial Cells/metabolism
MH  - Ligands
MH  - Mice
MH  - *MicroRNAs/genetics/metabolism
MH  - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors
MH  - Neointima/genetics/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Receptors, CXCR4/metabolism
MH  - Signal Transduction
PMC - PMC9208476
OTO - NOTNLM
OT  - ERK1/2
OT  - Neointima formation
OT  - RGS16
OT  - endothelium repair
OT  - miR-126-3p
COIS- No potential conflict of interest was reported by the author(s).
EDAT- 2022/04/30 06:00
MHDA- 2022/05/03 06:00
PMCR- 2022/04/29
CRDT- 2022/04/29 04:22
PHST- 2022/04/29 04:22 [entrez]
PHST- 2022/04/30 06:00 [pubmed]
PHST- 2022/05/03 06:00 [medline]
PHST- 2022/04/29 00:00 [pmc-release]
AID - 2063496 [pii]
AID - 10.1080/21655979.2022.2063496 [doi]
PST - ppublish
SO  - Bioengineered. 2022 Apr;13(4):11214-11227. doi: 10.1080/21655979.2022.2063496.