SIRT3 sulfhydration using hydrogen sulfide inhibited angiotensin II-induced atrial fibrosis and vulnerability to atrial fibrillation via suppression of the TGF-β1/smad2/3 signalling pathway

Eur J Pharmacol. 2024 Nov 5:982:176900. doi: 10.1016/j.ejphar.2024.176900. Epub 2024 Aug 19.

Abstract

Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-β1 (TGF-β1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-β1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-β1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-β1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-β1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.

Keywords: Angiotensin-II; Atrial fibrillation; SIRT3 sulfhydration; Sirtuin3; TGF-β1/Smad2/3.

MeSH terms

  • Aged
  • Angiotensin II* / pharmacology
  • Animals
  • Atrial Fibrillation* / metabolism
  • Atrial Fibrillation* / pathology
  • Atrial Fibrillation* / prevention & control
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Female
  • Fibrosis*
  • Heart Atria* / drug effects
  • Heart Atria* / metabolism
  • Heart Atria* / pathology
  • Humans
  • Hydrogen Sulfide* / metabolism
  • Hydrogen Sulfide* / pharmacology
  • Male
  • Middle Aged
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Sirtuin 3* / genetics
  • Sirtuin 3* / metabolism
  • Smad2 Protein* / metabolism
  • Smad3 Protein* / metabolism
  • Transforming Growth Factor beta1* / metabolism

Substances

  • Angiotensin II
  • Hydrogen Sulfide
  • SIRT3 protein, human
  • Sirtuin 3
  • Smad2 Protein
  • SMAD2 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • SMAD3 protein, human
  • TGFB1 protein, human