PMID- 32734582
OWN - NLM
STAT- MEDLINE
DCOM- 20210303
LR  - 20240516
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Print)
IS  - 1420-682X (Linking)
VI  - 78
IP  - 4
DP  - 2021 Feb
TI  - NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell 
      recruitment.
PG  - 1709-1727
LID - 10.1007/s00018-020-03607-7 [doi]
AB  - Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell 
      infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether 
      the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family 
      member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency 
      significantly attenuated elastase-induced and HHcy-aggravated murine AAA with 
      decreased T cell infiltration in the vessel walls. T cell labeling and adoptive 
      transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of 
      vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced 
      the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA 
      metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse 
      model of AAA, ATX was specifically expressed in the endothelium and the plasma 
      ATX concentration was upregulated and even higher in the HHcy group, which were 
      decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed 
      that ATX dose-dependently promoted T cell migration. HHcy may upregulate 
      endothelial ATX expression and secretion and in turn recruit T cells into the 
      vessel walls to induce vascular inflammation and consequently accelerate the 
      pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by 
      binding to integrin alpha4, which subsequently activated downstream FAK/Src-RhoA 
      signaling pathways and then induced T cell chemokinesis and adhesion. ATX 
      overexpression in the vessel walls reversed the inhibited development of AAA in 
      the NSun2-deficient mice. Therefore, NSun2 mediates the development of 
      HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion 
      and T cell migration, which is a novel mechanism for HHcy-aggravated vascular 
      inflammation and pathogenesis of AAA.
FAU - Miao, Yutong
AU  - Miao Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Zhao, Yang
AU  - Zhao Y
AD  - Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 
      People's Republic of China.
FAU - Han, Lulu
AU  - Han L
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Ma, Xiaolong
AU  - Ma X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Deng, Jiacheng
AU  - Deng J
AD  - Cardiovascular Division, BHF Center for Vascular Regeneration, King's College 
      London, London, UK.
FAU - Yang, Juan
AU  - Yang J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Lu, Silin
AU  - Lu S
AD  - State Key Laboratory of Bioactive Substances and Function of Natural Medicine, 
      Institute of Materia Medica, Peking Union Medical College, Chinese Academy of 
      Medical Sciences, Beijing, People's Republic of China.
FAU - Shao, Fangyu
AU  - Shao F
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Kong, Wei
AU  - Kong W
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China.
FAU - Wang, Wengong
AU  - Wang W
AD  - Department of Biochemistry and Molecular Biology, School of Basic Medical 
      Sciences, Peking University, Beijing, People's Republic of China.
FAU - Xu, Qingbo
AU  - Xu Q
AD  - Cardiovascular Division, BHF Center for Vascular Regeneration, King's College 
      London, London, UK.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China. xwang@bjmu.edu.cn.
FAU - Feng, Juan
AU  - Feng J
AUID- ORCID: 0000-0003-0174-4784
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, 100191, People's Republic of China. juanfeng@bjmu.edu.cn.
LA  - eng
GR  - 81670413/National Natural Science Foundation of China/
GR  - 91739303/National Natural Science Foundation of China/
GR  - 91939105/National Natural Science Foundation of China/
GR  - 81770445/National Natural Science Foundation of China/
GR  - 81700648/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20200730
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.- (Misu protein, mouse)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
SB  - IM
MH  - Animals
MH  - Aortic Aneurysm, Abdominal/complications/*genetics/immunology/pathology
MH  - Cell Movement/genetics
MH  - Disease Models, Animal
MH  - Endothelial Cells/immunology/metabolism
MH  - Gene Expression Regulation/genetics
MH  - Humans
MH  - Hyperhomocysteinemia/complications/*genetics/pathology
MH  - Inflammation/complications/*genetics/pathology
MH  - Methyltransferases/*genetics
MH  - Mice
MH  - Phosphoric Diester Hydrolases/*genetics
MH  - Signal Transduction/genetics
MH  - T-Lymphocytes/immunology/metabolism
PMC - PMC11073013
OTO - NOTNLM
OT  - ATX
OT  - Abdominal aortic aneurysm
OT  - Endothelial cells
OT  - NSun2
OT  - T cells
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/08/01 06:00
MHDA- 2021/03/04 06:00
PMCR- 2020/07/30
CRDT- 2020/08/01 06:00
PHST- 2020/02/22 00:00 [received]
PHST- 2020/07/22 00:00 [accepted]
PHST- 2020/07/09 00:00 [revised]
PHST- 2020/08/01 06:00 [pubmed]
PHST- 2021/03/04 06:00 [medline]
PHST- 2020/08/01 06:00 [entrez]
PHST- 2020/07/30 00:00 [pmc-release]
AID - 10.1007/s00018-020-03607-7 [pii]
AID - 3607 [pii]
AID - 10.1007/s00018-020-03607-7 [doi]
PST - ppublish
SO  - Cell Mol Life Sci. 2021 Feb;78(4):1709-1727. doi: 10.1007/s00018-020-03607-7. 
      Epub 2020 Jul 30.