Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation

J Hypertens. 2022 Apr 1;40(4):765-775. doi: 10.1097/HJH.0000000000003075.

Abstract

Background: Angiotensin (Ang) II and elevated blood pressure are considered to be the main risk factors for atrial fibrillation. However, the proteome profiles and key mediators/signaling pathways involved in the development of Ang II-induced atrial fibrillation remain unclear.

Methods: Male wild-type C57BL/6 mice (10-week old) were infused with Ang II (2000 ng/kg per min) for 1, 2, or 3 weeks, respectively. Time series proteome profiling of atrial tissues was performed using isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry.

Results: We identified a total of 1566 differentially expressed proteins (DEPs) in the atrial tissues at weeks 1, 2, and 3 after Ang II infusion. These DEPs were predominantly involved in mitochondrial oxidation-reduction and tricarboxylic acid cycle in Ang II-infused atria. Moreover, coexpression network analysis revealed that citrate synthase, a rate-limiting enzyme in the tricarboxylic acid cycle, was localized at the center of the mitochondrial oxidation-reduction process, and its expression was significantly downreguated in Ang II-infused atria at different time points. Cardiomyocyte-specific overexpresion of citrate synthase markedly reduced atrial fibrillation susceptibility and atrial remodeling in mice. These beneficial effects were associated with increased ATP production and mitochondrial oxidative phosphorylation system complexes I-V expression and inhibition of oxidative stress.

Conclusion: The current study defines the dynamic changes of the DEPs involved in Ang II-induced atrial fibrillation, and identifies that citrate synthase plays a protective role in regulating atrial fibrillation development, and increased citrate synthase expression may represent a potential therapeutic option for atrial fibrillation treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II* / pharmacology
  • Animals
  • Atrial Fibrillation* / chemically induced
  • Atrial Fibrillation* / drug therapy
  • Citrate (si)-Synthase
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proteome
  • Time Factors

Substances

  • Proteome
  • Angiotensin II
  • Citrate (si)-Synthase