Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE.
Lung-An HsuFeng-Chun TsaiYung-Hsin YehChi-Jen ChangChi-Tai KuoWei-Jan ChenHsin-Yi TsaiGwo-Jyh ChangPublished in: International journal of molecular sciences (2020)
Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2, a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.
Keyphrases
- atrial fibrillation
- alcohol consumption
- left atrial
- catheter ablation
- diabetic rats
- oral anticoagulants
- transforming growth factor
- direct oral anticoagulants
- left atrial appendage
- reactive oxygen species
- high glucose
- wild type
- oxidative stress
- crispr cas
- heart failure
- drug induced
- minimally invasive
- dna damage
- percutaneous coronary intervention
- systematic review
- epithelial mesenchymal transition
- gene expression
- type diabetes
- dna methylation
- skeletal muscle
- genome editing
- meta analyses
- pulmonary hypertension
- lymph node
- randomized controlled trial
- left ventricular
- young adults
- high frequency
- radiation therapy
- replacement therapy
- heat shock