PMID- 35966575
OWN - NLM
STAT- MEDLINE
DCOM- 20220816
LR  - 20220824
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 12
IP  - 13
DP  - 2022
TI  - LRRC8A critically regulates myofibroblast phenotypes and fibrotic remodeling 
      following myocardial infarction.
PG  - 5824-5835
LID - 10.7150/thno.75200 [doi]
AB  - Rationale: The transformation of fibroblasts into activated myofibroblasts is a 
      critical step that results in cardiac fibrosis upon myocardial infarction (MI). 
      Leucine-rich repeat-containing protein-8A (LRRC8A) is a multi-functional protein 
      involved in cell survival, growth, and proliferation, whereas its role in 
      regulating myofibroblast phenotypes and myocardial fibrosis remains unknown. 
      Methods: Conditional myofibroblast-specific Lrrc8a knockout mouse models were 
      established by crossing the Lrrc8a(flox/flox) mice with the tamoxifen-inducible 
      periostin-Cre transgenic mice. The involvement of LRRC8A in regulating cardiac 
      fibrosis post-MI and myofibroblast phenotypes induced by transforming growth 
      factor-beta1 (TGF-beta1) was comprehensively evaluated. The mechanisms underlying 
      LRRC8A regulation of myofibroblast phenotypes were determined by RNA 
      sequencing-driven analysis followed by cause-effect experiments. Results: LRRC8A 
      expression was significantly elevated in the fibrotic tissues and the fibroblasts 
      isolated from the post-MI hearts. Compared with the wild-type (WT) littermates, 
      the specific knockout of LRRC8A in myofibroblasts greatly attenuated 
      myofibroblast transformation, fibrotic remodeling, and ventricular dysfunction 
      after MI. Silencing of LRRC8A expression suppressed, whereas overexpression of 
      LRRC8A enhanced, the pro-fibrotic myofibroblast phenotypes in isolated cardiac 
      fibroblasts upon stimulation with TGF-beta1. LRRC8A participated in TGF-beta1-induced 
      myofibroblast transformation via activating JAK2-STAT3 signaling. Furthermore, 
      LRRC8A activated the JAK2-STAT3 pathway via its C-terminal leucine-rich 
      repeat-domain (LRRD), directly interacting with growth factor receptor-bound 
      protein 2 (GRB2), an adaptor protein associated with and necessary for 
      tyrosine-phosphorylated JAK2. Conclusions: LRRC8A regulates myofibroblast 
      transformation and cardiac fibrosis following MI. LRRC8A inhibition might be a 
      promising strategy for cardiac fibrosis and heart failure.
CI  - (c) The author(s).
FAU - Chen, Xiyao
AU  - Chen X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Zhang, Fuyang
AU  - Zhang F
AD  - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Hu, Guangyu
AU  - Hu G
AD  - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Li, Xing
AU  - Li X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Wang, Lin
AU  - Wang L
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Li, Congye
AU  - Li C
AD  - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Huo, Cong
AU  - Huo C
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Xu, Rong
AU  - Xu R
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Hou, Liming
AU  - Hou L
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Wang, Ning
AU  - Wang N
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
FAU - Wang, Xiaoming
AU  - Wang X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032 China.
LA  - eng
PT  - Journal Article
DEP - 20220727
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Carrier Proteins)
RN  - 0 (LRRC8A protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Transforming Growth Factor beta1)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - Fibrosis
MH  - Leucine/genetics/metabolism
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - *Myocardial Infarction/genetics/metabolism
MH  - *Myofibroblasts/metabolism
MH  - Phenotype
MH  - Transforming Growth Factor beta1/metabolism
PMC - PMC9373806
OTO - NOTNLM
OT  - fibrosis
OT  - heart failure
OT  - leucine-rich repeat-containing protein 8A
OT  - myocardial infarction
OT  - myofibroblast.
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2022/08/16 06:00
MHDA- 2022/08/17 06:00
PMCR- 2022/01/01
CRDT- 2022/08/15 03:44
PHST- 2022/05/16 00:00 [received]
PHST- 2022/07/03 00:00 [accepted]
PHST- 2022/08/15 03:44 [entrez]
PHST- 2022/08/16 06:00 [pubmed]
PHST- 2022/08/17 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - thnov12p5824 [pii]
AID - 10.7150/thno.75200 [doi]
PST - epublish
SO  - Theranostics. 2022 Jul 27;12(13):5824-5835. doi: 10.7150/thno.75200. eCollection 
      2022.