Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.
Biao LiSunny S PoBaojian ZhangFan BaiJiayi LiFen QinNa LiuChao SunYichao XiaoTao TuShenghua ZhouQi Ming LiuPublished in: Journal of cellular and molecular medicine (2020)
Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP-induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa-B (NF-κB) phosphorylation; up-regulated interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) levels in LA and EAT; decreased peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL-6, TNF-α and TGF-β1 expression and decreased PPARγ/APN expression in 3T3-L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL-1 cells with LPS-stimulated 3T3-L1 conditioned medium (CM) significantly increased IL-6, TNF-α and TGF-β1 expression and decreased SERCA2a and p-PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP-induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF-dependent EAT remodelling and AF vulnerability by MET.
Keyphrases
- atrial fibrillation
- catheter ablation
- inflammatory response
- transforming growth factor
- adipose tissue
- left atrial appendage
- poor prognosis
- left atrial
- nuclear factor
- oral anticoagulants
- insulin resistance
- climate change
- direct oral anticoagulants
- tyrosine kinase
- heart failure
- rheumatoid arthritis
- toll like receptor
- percutaneous coronary intervention
- binding protein
- reactive oxygen species
- epithelial mesenchymal transition
- lps induced
- long non coding rna
- metabolic syndrome
- induced apoptosis
- type diabetes
- oxidative stress
- high fat diet
- cell death
- coronary artery disease
- cell cycle arrest
- diabetic rats
- inferior vena cava
- vena cava
- idiopathic pulmonary fibrosis
- cell proliferation
- replacement therapy
- disease activity
- clinical trial
- dna damage
- double blind