Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Dronedarone Attenuates Ang II-Induced Myocardial Hypertrophy Through Regulating SIRT1/FOXO3/PKIA Axis

  • Cheng Chen (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Song Hu (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Heng-Jing Hu (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Zhi-Xuan Liu (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Xin-Teng Wu (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Tao Zou (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China) ;
  • Hua Su (Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China)
  • Received : 2023.07.11
  • Accepted : 2024.01.23
  • Published : 2024.04.01
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Abstract

Background and Objectives: Long-term pathological myocardial hypertrophy (MH) seriously affects the normal function of the heart. Dronedarone was reported to attenuate left ventricular hypertrophy of mice. However, the molecular regulatory mechanism of dronedarone in MH is unclear. Methods: Angiotensin II (Ang II) was used to induce cell hypertrophy of H9C2 cells. Transverse aortic constriction (TAC) surgery was performed to establish a rat model of MH. Cell size was evaluated using crystal violet staining and rhodamine phalloidin staining. Reverse transcription quantitative polymerase chain reaction and western blot were performed to detect the mRNA and protein expressions of genes. JASPAR and luciferase activity were conducted to predict and validate interaction between forkhead box O3 (FOXO3) and protein kinase inhibitor alpha (PKIA) promoter. Results: Ang II treatment induced cell hypertrophy and inhibited sirtuin 1 (SIRT1) expression, which were reversed by dronedarone. SIRT1 overexpression or PKIA overexpression enhanced dronedarone-mediated suppression of cell hypertrophy in Ang II-induced H9C2 cells. Mechanistically, SIRT1 elevated FOXO3 expression through SIRT1- mediated deacetylation of FOXO3 and FOXO3 upregulated PKIA expression through interacting with PKIA promoter. Moreover, SIRT1 silencing compromised dronedarone-mediated suppression of cell hypertrophy, while PKIA upregulation abolished the influences of SIRT1 silencing. More importantly, dronedarone improved TAC surgery-induced MH and impairment of cardiac function of rats via affecting SIRT1/FOXO3/PKIA axis. Conclusions: Dronedarone alleviated MH through mediating SIRT1/FOXO3/PKIA axis, which provide more evidences for dronedarone against MH.

Keywords

Acknowledgement

This work was supported by Hunan Provincial Nature (No. 2019JJ40264): Effects of H2S on cardiac Warburg effect and atrial fibrillation through sulfhydrylation of PKM2 and Hunan Provincial Health Commission project (No. C202303019609): Effects of H2S targeting miR-133a mediating TGF-β1 pathway on atrial fibrillation and atrial fibrosis.

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