PMID- 37271038
OWN - NLM
STAT- MEDLINE
DCOM- 20230616
LR  - 20230618
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 670
DP  - 2023 Aug 30
TI  - RHOJ as a novel mechanosensitive modulator of endothelial inflammation.
PG  - 36-46
LID - S0006-291X(23)00686-1 [pii]
LID - 10.1016/j.bbrc.2023.05.099 [doi]
AB  - Physiological high shear stress (HSS), a frictional force generated by flowing 
      blood, is essential for endothelial homeostasis under normal physiological 
      conditions. HSS suppresses atherosclerosis by inhibiting endothelial 
      inflammation. However, the molecular mechanisms underlying this process have not 
      been fully elucidated. Here, we report that HSS downregulated the mRNA and 
      protein levels of ras homolog family member J (RHOJ) in endothelial cells (ECs). 
      Silencing endogenous RHOJ expression decreased the mRNA and protein levels of 
      proinflammatory vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell 
      adhesion molecule 1 (ICAM-1) in ECs, leading to a reduction in monocyte adhesion 
      to ECs. Conversely, the overexpression of RHOJ had the opposite effect. 
      RNA-sequencing analysis uncovered several differentially expressed genes (such as 
      yes-associated protein 1 (YAP1),heme oxygenase-1 (HO1), and monocyte 
      chemoattractant protein-1 (MCP1)) and pathways (such as nuclear factor-kappa B 
      (NF-kappaB), fluid shear stress and atherosclerosis, and cell adhesion pathways) as 
      RHOJ targets. Additionally, HSS was observed to alleviate endothelial 
      inflammation by inhibiting RHOJ expression. Finally, methylated RNA 
      immunoprecipitation sequencing (MeRIP-seq) illustrated that fluid shear stress 
      regulates RHOJ expression in an N6-methyladenosine (m6A)-dependent manner. 
      Mechanistically, the RNA m6A writer, methyltransferase 3 (METTL3), and the RNA 
      m6A readers, YTH N6-methyladenosine RNA-binding protein F 3 (YTHDF3) and YTH 
      N6-methyladenosine RNA-binding protein C 1/2 (YTHDC1/2), are involved in this 
      process. Taken together, our data demonstrate that HSS-induced downregulation of 
      RHOJ contributes to endothelial homeostasis by suppressing endothelial 
      inflammation and that RHOJ inhibition in ECs is a promising therapeutic strategy 
      for endothelial dysfunction.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Liu, WenQiang
AU  - Liu W
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China.
FAU - Zeng, Yue
AU  - Zeng Y
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China.
FAU - Huang, LiHan
AU  - Huang L
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China.
FAU - Zhang, XiaoZhe
AU  - Zhang X
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China.
FAU - Bi, LianRu
AU  - Bi L
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China.
FAU - Fan, WenDong
AU  - Fan W
AD  - Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, 510080, Guangdong, PR China; NHC Key Laboratory of 
      Assisted Circulation (Sun Yat-sen University), PR China. Electronic address: 
      fanwd3@mail.sysu.edu.cn.
FAU - Wu, GuiFu
AU  - Wu G
AD  - Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen 
      University, Shenzhen, 518033, Guangdong, PR China; NHC Key Laboratory of Assisted 
      Circulation (Sun Yat-sen University), PR China; Guangdong Innovative Engineering 
      and Technology Research Center for Assisted Circulation, PR China. Electronic 
      address: wuguifu@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230526
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 63231-63-0 (RNA)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - EC 2.1.1.62 (METTL3 protein, human)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 3.6.1.- (RHOJ protein, human)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Humans
MH  - *Endothelial Cells/metabolism
MH  - Inflammation/genetics/metabolism
MH  - RNA/metabolism
MH  - RNA, Messenger/metabolism
MH  - *Atherosclerosis/genetics/metabolism
MH  - RNA-Binding Proteins/metabolism
MH  - Methyltransferases/metabolism
MH  - rho GTP-Binding Proteins/metabolism
OTO - NOTNLM
OT  - Inflammation
OT  - N6-methyladenosine
OT  - Ras homolog family member J
OT  - Shear stress
OT  - Vascular endothelial cells
COIS- Declaration of competing interest The authors declare no conflicts of interest.
EDAT- 2023/06/05 00:42
MHDA- 2023/06/16 06:42
CRDT- 2023/06/04 18:07
PHST- 2023/04/22 00:00 [received]
PHST- 2023/05/25 00:00 [accepted]
PHST- 2023/06/16 06:42 [medline]
PHST- 2023/06/05 00:42 [pubmed]
PHST- 2023/06/04 18:07 [entrez]
AID - S0006-291X(23)00686-1 [pii]
AID - 10.1016/j.bbrc.2023.05.099 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2023 Aug 30;670:36-46. doi: 
      10.1016/j.bbrc.2023.05.099. Epub 2023 May 26.