Omentin-1 attenuates atrial fibrillation via Src/PI3K/Akt signaling-mediated anti-fibrotic effects in cardiac fibroblasts.

Background: Atrial fibrillation (AF) is characterized by progressive atrial fibrosis, leading to increased morbidity and mortality. While the novel adipokine Omentin-1 demonstrates anti-fibrotic potential across organ systems, its role in AF pathogenesis remains unclear. This study investigates Omentin-1's therapeutic effects and the underlying mechanisms in angiotensin II (Ang II)-induced atrial fibrosis and AF.

Methods: Atrial fibrosis was induced in C57BL/6 mice via continuous Ang II infusion for 4 weeks. Omentin-1 overexpression was achieved using adeno-associated virus serotype 2/9 (AAV2/9). AF susceptibility was assessed by programmed electrical stimulation, and atrial fibrosis was quantified using histological staining and Western blot analysis. Immunofluorescence co-localization assessed cell-type specific expression of Omentin-1, and proteomic analysis of atrial fibroblasts was conducted to explore molecular pathways involved. In vitro studies using primary fibroblasts were conducted to validate Omentin-1's effects.

Results: Omentin-1 levels were significantly decreased in both serum and atrial tissue of Ang II-treated mice. Omentin-1 overexpression reduced AF inducibility, decreased atrial fibrosis, and improved left atrial strain parameters. Immunofluorescence showed that Omentin-1 predominantly localized to atrial fibroblasts. Mechanistically, Omentin-1 regulated collagen metabolism by targeting fibroblasts, with Src kinase acting as a critical mediator of fibroblast activation through the PI3K/Akt signaling pathway.

Conclusion: Omentin-1 attenuates atrial fibrosis and AF susceptibility through regulation of the Src/PI3K/Akt signaling pathway in atrial fibroblasts. These findings suggest that Omentin-1 may represent a potential therapeutic target for the prevention and treatment of AF.