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http://purl.uniprot.org/citations/33332716http://www.w3.org/2000/01/rdf-schema#comment"

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 (IKATP ), mitochondrial oxidative stress, Ca2+ 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, IKATP , phosphorylated adenosine monophosphate-activated protein kinase and inositol 1,4,5-triphosphate (IP3 ) receptor (IP3 R) protein expression. Tachypacing induced mitochondrial oxidative stress and Ca2+ overload in both cell types. Furthermore, under 1- and 5-Hz pacing, ZFHX3 KD cells showed higher IKATP , ATP and ADP production, mitochondrial oxidative stress and Ca2+ content than control cells. Under 5-Hz pacing, 2-aminoethoxydiphenyl borate (2-APB; 3 μmol/L, an IP3 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 Ca2+ 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 Ca2+ overload, oxidative stress and metabolic disorder. Targeting IP3 R signalling or oxidative stress could reduce AF."xsd:string
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http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Chen Y.C."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Chen Y.J."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Lin Y.K."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Higa S."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Kao Y.H."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Cheng W.L."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/author"Lkhagva B."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/name"Acta Physiol (Oxf)"xsd:string
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http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/title"ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial myocytes through enhanced oxidative stress and calcium overload."xsd:string
http://purl.uniprot.org/citations/33332716http://purl.uniprot.org/core/volume"231"xsd:string
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