PMID- 33515753
OWN - NLM
STAT- MEDLINE
DCOM- 20210628
LR  - 20210628
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 165
DP  - 2021 Mar
TI  - LRRC8A contributes to angiotensin II-induced cardiac hypertrophy by interacting 
      with NADPH oxidases via the C-terminal leucine-rich repeat domain.
PG  - 191-202
LID - S0891-5849(21)00039-3 [pii]
LID - 10.1016/j.freeradbiomed.2021.01.022 [doi]
AB  - Cardiac hypertrophy, an important cause of heart failure, is characterized by an 
      increase in heart weight, the ventricular wall, and cardiomyocyte volume. The 
      volume regulatory anion channel (VRAC) is an important regulator of cell volume. 
      However, its role in cardiac hypertrophy remains unclear. The purpose of this 
      study was to investigate the effect of leucine-rich repeat-containing 8A 
      (LRRC8A), an essential component of the VRAC, on angiotensin II (AngII)-induced 
      cardiac hypertrophy. Our results showed that LRRC8A expression, NADPH oxidase 
      activity, and reactive oxygen species (ROS) production were increased in 
      AngII-induced hypertrophic neonatal mouse cardiomyocytes and the myocardium of 
      C57/BL/6 mice. In addition, AngII activated VRAC currents in cardiomyocytes. The 
      delivery of adeno-associated viral (AAV9) bearing siRNA against mouse LRRC8A into 
      the left ventricular wall inhibited AngII-induced cardiac hypertrophy and 
      fibrosis. Accordingly, the knockdown of LRRC8A attenuated AngII-induced 
      cardiomyocyte hypertrophy and VRAC currents in vitro. Furthermore, knockdown of 
      LRRC8A suppressed AngII-induced ROS production, NADPH oxidase activity, the 
      expression of NADPH oxidase membrane-bound subunits Nox2, Nox4, and p22phox, and 
      the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox. 
      Immunofluorescent staining showed that LRRC8A co-localized with NADPH oxidase 
      membrane subunits Nox2, Nox4, and p22phox. Co-immunoprecipitation and analysis of 
      a C-terminal leucine-rich repeat domain (LRRD) mutant showed that LRRC8A 
      physically interacts with Nox2, Nox4, and p22phox via the LRRD. Taken together, 
      the results of this study suggested that LRRC8A might play an important role in 
      promoting AngII-induced cardiac hypertrophy by interacting with NADPH oxidases 
      via the LRRD.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Huo, Cong
AU  - Huo C
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Liu, Yan
AU  - Liu Y
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Li, Xing
AU  - Li X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Xu, Rong
AU  - Xu R
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Jia, Xin
AU  - Jia X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Hou, Liming
AU  - Hou L
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China.
FAU - Wang, Xiaoming
AU  - Wang X
AD  - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 
      Xi'an, 710032, PR China. Electronic address: xmwang@fmmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210127
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (LRRC8A protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - *Angiotensin II/toxicity
MH  - Animals
MH  - Cardiomegaly/chemically induced/genetics
MH  - Leucine
MH  - Membrane Proteins/genetics
MH  - Mice
MH  - *NADPH Oxidases/genetics
MH  - Reactive Oxygen Species
OTO - NOTNLM
OT  - Angiotensin II
OT  - Cardiac hypertrophy
OT  - Leucine-rich repeat containing 8A
OT  - NADPH oxidase
OT  - Reactive oxygen species
OT  - Volume regulatory anion channel
EDAT- 2021/01/31 06:00
MHDA- 2021/06/29 06:00
CRDT- 2021/01/30 20:09
PHST- 2020/12/10 00:00 [received]
PHST- 2021/01/08 00:00 [revised]
PHST- 2021/01/10 00:00 [accepted]
PHST- 2021/01/31 06:00 [pubmed]
PHST- 2021/06/29 06:00 [medline]
PHST- 2021/01/30 20:09 [entrez]
AID - S0891-5849(21)00039-3 [pii]
AID - 10.1016/j.freeradbiomed.2021.01.022 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2021 Mar;165:191-202. doi: 
      10.1016/j.freeradbiomed.2021.01.022. Epub 2021 Jan 27.