PMID- 36139452
OWN - NLM
STAT- MEDLINE
DCOM- 20220926
LR  - 20230418
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 18
DP  - 2022 Sep 15
TI  - Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis.
LID - 10.3390/cells11182877 [doi]
LID - 2877
AB  - Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, 
      are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic 
      inflammation and lipid-laden macrophage foam cell formation are the central 
      pathogeneses in the development of atherosclerosis. This study was undertaken to 
      illustrate the biological function of TM6SF2 in macrophages and its role during 
      atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout 
      mice on ApoE-deficient background (LysM Cre+/Tm6sf2(fl/fl)/ApoE(-/-), TM6 mKO) 
      with littermate LysM Cre-/Tm6sf2(fl/fl)/ApoE(-/-) (Control) mice as controls. 
      Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid 
      Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the 
      plaques without changing the plasma lipid profile. RNA sequencing of bone 
      marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the 
      downregulation of genes associated with inflammation, cholesterol uptake, and 
      endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density 
      lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages 
      and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and 
      attenuated cholesterol uptake and foam cell formation, while the overexpression 
      of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency 
      inhibits atherosclerosis development and is a potential therapeutic target for 
      the treatment of atherogenesis.
FAU - Zhu, Wenzhen
AU  - Zhu W
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
FAU - Liang, Wenying
AU  - Liang W
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
FAU - Lu, Haocheng
AU  - Lu H
AUID- ORCID: 0000-0002-5740-8010
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
AD  - Department of Pharmacology, Southern University of Science and Technology, 
      Shenzhen 518055, China.
FAU - Chang, Lin
AU  - Chang L
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
FAU - Zhang, Jifeng
AU  - Zhang J
AUID- ORCID: 0000-0001-5161-4705
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
FAU - Chen, Y Eugene
AU  - Chen YE
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
FAU - Guo, Yanhong
AU  - Guo Y
AUID- ORCID: 0000-0002-3334-9159
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI 48109, USA.
LA  - eng
GR  - R01 HL138139/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220915
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Membrane Proteins)
RN  - 0 (Tm6sf2 protein, mouse)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - *Atherosclerosis/genetics
MH  - Cholesterol
MH  - Inflammation
MH  - Lipoproteins, LDL
MH  - *Membrane Proteins/genetics
MH  - Mice
MH  - Mice, Knockout, ApoE
PMC - PMC9497156
OTO - NOTNLM
OT  - ER stress
OT  - TM6SF2
OT  - atherosclerosis
OT  - cholesterol
OT  - inflammation
OT  - macrophage
COIS- The authors declare no conflict of interest.
EDAT- 2022/09/24 06:00
MHDA- 2022/09/28 06:00
PMCR- 2022/09/15
CRDT- 2022/09/23 01:06
PHST- 2022/08/25 00:00 [received]
PHST- 2022/09/07 00:00 [revised]
PHST- 2022/09/09 00:00 [accepted]
PHST- 2022/09/23 01:06 [entrez]
PHST- 2022/09/24 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/09/15 00:00 [pmc-release]
AID - cells11182877 [pii]
AID - cells-11-02877 [pii]
AID - 10.3390/cells11182877 [doi]
PST - epublish
SO  - Cells. 2022 Sep 15;11(18):2877. doi: 10.3390/cells11182877.