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

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.