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ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial myocytes through enhanced oxidative stress and calcium overload.
- Source :
-
Acta physiologica (Oxford, England) [Acta Physiol (Oxf)] 2021 Apr; Vol. 231 (4), pp. e13604. Date of Electronic Publication: 2020 Dec 29. - Publication Year :
- 2021
-
Abstract
- 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).<br />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 <subscript>KATP</subscript> ), mitochondrial oxidative stress, Ca <superscript>2+</superscript> content, and protein expression in control and ZFHX3 knockdown (KD) HL-1 cells subjected to 1 and 5-Hz pacing for 24 hours.<br />Results: Compared with 1-Hz pacing, 5-Hz pacing increased ATP and ADP production, I <subscript>KATP</subscript> , phosphorylated adenosine monophosphate-activated protein kinase and inositol 1,4,5-triphosphate (IP <subscript>3</subscript> ) receptor (IP <subscript>3</subscript> R) protein expression. Tachypacing induced mitochondrial oxidative stress and Ca <superscript>2+</superscript> overload in both cell types. Furthermore, under 1- and 5-Hz pacing, ZFHX3 KD cells showed higher I <subscript>KATP</subscript> , ATP and ADP production, mitochondrial oxidative stress and Ca <superscript>2+</superscript> content than control cells. Under 5-Hz pacing, 2-aminoethoxydiphenyl borate (2-APB; 3 μmol/L, an IP <subscript>3</subscript> R inhibitor) and MitoTEMPO (10 µmol/L, a mitochondria-targeted antioxidant) reduced ADP and increased ATP production in both cell types; however, only 2-APB significantly reduced mitochondrial Ca <superscript>2+</superscript> 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.<br />Conclusion: ZFHX3 KD cells modulate mitochondrial adaptations to tachypacing in HL-1 cardiomyocytes through Ca <superscript>2+</superscript> overload, oxidative stress and metabolic disorder. Targeting IP <subscript>3</subscript> R signalling or oxidative stress could reduce AF.<br /> (© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)
Details
- Language :
- English
- ISSN :
- 1748-1716
- Volume :
- 231
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Acta physiologica (Oxford, England)
- Publication Type :
- Academic Journal
- Accession number :
- 33332716
- Full Text :
- https://doi.org/10.1111/apha.13604