PMID- 33332716
OWN - NLM
STAT- MEDLINE
DCOM- 20210818
LR  - 20220531
IS  - 1748-1716 (Electronic)
IS  - 1748-1708 (Linking)
VI  - 231
IP  - 4
DP  - 2021 Apr
TI  - ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial 
      myocytes through enhanced oxidative stress and calcium overload.
PG  - e13604
LID - 10.1111/apha.13604 [doi]
AB  - AIM: To investigate the role of zinc finger homeobox 3 gene (ZFHX3) in 
      tachypacing-induced mitochondrial dysfunction and explore its molecular 
      mechanisms and potential as a therapeutic target in atrial fibrillation (AF). 
      METHODS: Through a bioluminescent assay, a patch clamp, confocal fluorescence and 
      fluorescence microscopy, microplate enzyme activity assays and Western blotting, 
      we studied ATP and ADP production, mitochondrial electron transfer chain complex 
      activities, ATP-sensitive potassium channels (I(KATP) ), mitochondrial oxidative 
      stress, Ca(2+) content, and protein expression in control and ZFHX3 knockdown 
      (KD) HL-1 cells subjected to 1 and 5-Hz pacing for 24 hours. RESULTS: Compared 
      with 1-Hz pacing, 5-Hz pacing increased ATP and ADP production, I(KATP) , 
      phosphorylated adenosine monophosphate-activated protein kinase and inositol 
      1,4,5-triphosphate (IP(3) ) receptor (IP(3) R) protein expression. Tachypacing 
      induced mitochondrial oxidative stress and Ca(2+) overload in both cell types. 
      Furthermore, under 1- and 5-Hz pacing, ZFHX3 KD cells showed higher I(KATP) , ATP 
      and ADP production, mitochondrial oxidative stress and Ca(2+) content than 
      control cells. Under 5-Hz pacing, 2-aminoethoxydiphenyl borate (2-APB; 3 mumol/L, 
      an IP(3) R inhibitor) and MitoTEMPO (10 micromol/L, a mitochondria-targeted 
      antioxidant) reduced ADP and increased ATP production in both cell types; 
      however, only 2-APB significantly reduced mitochondrial Ca(2+) overload in 
      control cells. Under 5-Hz pacing, mitochondrial oxidative stress was 
      significantly reduced by both MitoTEMPO and 2-APB and only by 2-APB in control 
      and ZFHX3 KD cells respectively. CONCLUSION: ZFHX3 KD cells modulate 
      mitochondrial adaptations to tachypacing in HL-1 cardiomyocytes through Ca(2+) 
      overload, oxidative stress and metabolic disorder. Targeting IP(3) R signalling 
      or oxidative stress could reduce AF.
CI  - (c) 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
FAU - Lkhagva, Baigalmaa
AU  - Lkhagva B
AD  - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical 
      University, Taipei, Taiwan.
FAU - Lin, Yung-Kuo
AU  - Lin YK
AD  - Division of Cardiology, Department of Internal Medicine, School of Medicine, 
      College of Medicine, Taipei Medical University, Taipei, Taiwan.
FAU - Chen, Yao-Chang
AU  - Chen YC
AD  - Department of Biomedical Engineering, National Defense Medical Center, Taipei, 
      Taiwan.
FAU - Cheng, Wan-Li
AU  - Cheng WL
AD  - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical 
      University, Taipei, Taiwan.
FAU - Higa, Satoshi
AU  - Higa S
AD  - Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular 
      Medicine, Makiminato Central Hospital, Okinawa, Japan.
FAU - Kao, Yu-Hsun
AU  - Kao YH
AD  - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical 
      University, Taipei, Taiwan.
AD  - Department of Medical Education and Research, Wan-Fang Hospital, Taipei Medical 
      University, Taipei, Taiwan.
FAU - Chen, Yi-Jen
AU  - Chen YJ
AUID- ORCID: 0000-0001-7224-4491
AD  - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical 
      University, Taipei, Taiwan.
AD  - Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, 
      Taipei, Taiwan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201229
PL  - England
TA  - Acta Physiol (Oxf)
JT  - Acta physiologica (Oxford, England)
JID - 101262545
RN  - 0 (Homeodomain Proteins)
RN  - 143258-00-8 (ZFHX3 protein, human)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - *Atrial Fibrillation/metabolism
MH  - Calcium/metabolism
MH  - Homeodomain Proteins/metabolism
MH  - Humans
MH  - Mitochondria/metabolism
MH  - *Myocytes, Cardiac/metabolism
MH  - Oxidative Stress
OTO - NOTNLM
OT  - ZFHX3
OT  - atrial fibrillation
OT  - calcium
OT  - mitochondria
OT  - tachypacing
EDAT- 2020/12/18 06:00
MHDA- 2021/08/19 06:00
CRDT- 2020/12/17 17:21
PHST- 2020/12/06 00:00 [revised]
PHST- 2020/07/01 00:00 [received]
PHST- 2020/12/11 00:00 [accepted]
PHST- 2020/12/18 06:00 [pubmed]
PHST- 2021/08/19 06:00 [medline]
PHST- 2020/12/17 17:21 [entrez]
AID - 10.1111/apha.13604 [doi]
PST - ppublish
SO  - Acta Physiol (Oxf). 2021 Apr;231(4):e13604. doi: 10.1111/apha.13604. Epub 2020 
      Dec 29.