ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis.

Yu-Feng Hu, Chih-Hsun Wu, Tsung-Ching Lai, Yu-Chan Chang, Ming-Jing Hwang, Ting-Yung Chang, Ching-Hui Weng, Peter Mu-Hsin Chang, Che-Hong Chen, Daria Mochly-Rosen, Chi-Ying F Huang, Shih-Ann Chen

Biochimica et biophysica acta. Molecular basis of disease 2021 May 01

filter terms:

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid β-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Yu-Feng Hu, Chih-Hsun Wu, Tsung-Ching Lai, Yu-Chan Chang, Ming-Jing Hwang, Ting-Yung Chang, Ching-Hui Weng, Peter Mu-Hsin Chang, Che-Hong Chen, Daria Mochly-Rosen, Chi-Ying F Huang, Shih-Ann Chen. ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis. Biochimica et biophysica acta. Molecular basis of disease. 2021 May 01;1867(5):166088