ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial myocytes through enhanced oxidative stress and calcium overload. (29th December 2020)

• Record Type: Journal Article
• Authors: Lkhagva, Baigalmaa; Lin, Yung‐Kuo; Chen, Yao‐Chang; Cheng, Wan‐Li; Higa, Satoshi; Kao, Yu‐Hsun; Chen, Yi‐Jen
• Is Part Of: Acta physiologica. Volume 231:Number 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-29
• Subjects: atrial fibrillation -- calcium -- mitochondria -- tachypacing -- ZFHX3; Physiology -- Periodicals; Physiology -- Research -- Periodicals; 612
• DOI: 10.1111/apha.13604
• Languages: English
• ISSNs: 1748-1708

Abstract

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). 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, 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, 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 Ca 2+ 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 Ca 2+ 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 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 IP3 R signalling or oxidative stress could reduce AF.