Knockdown of ST2 alleviates atrial fibrillation-induced atrial fibrosis by suppressing autophagy

Atrial fibrosis is a key pathological factor in atrial fibrillation (AF), with abnormal inflammation and autophagy playing significant roles. The IL-33/ST2 axis regulates various inflammatory and fibrotic diseases, but its role in AF-induced atrial fibrosis remains unclear. This study aimed to elucidate the functional role of the IL-33/ST2 signaling axis in AF-induced atrial fibrosis and its impact on autophagy in atrial fibroblast activation. An AF rat model was established, and si-ST2 was injected into the left atrium. Inflammatory markers, fibrosis markers (α-SMA, Vimentin), and autophagy proteins (LC3, Beclin-1) were measured. In vitro, IL-17 and Ang II were used to simulate AF conditions in cultured atrial fibroblasts. After ST2 knockdown, cell proliferation, inflammatory responses, fibrosis, and autophagy were assessed. Rats in the AF model had significantly elevated inflammatory markers, white blood cell count, and fibrosis markers, with autophagy higher than controls (P < 0.01). Although these markers remained elevated compared to the control group (P < 0.05), ST2 knockdown dramatically decreased them compared to the AF model group (P < 0.01). In vitro, IL-17 and Ang II stimulation markedly promoted fibroblast proliferation, inflammation, fibrosis, and autophagy (P < 0.01), all of which were partially reversed by ST2 knockdown (P < 0.01). The partial reversal suggests that while the IL-33/ST2 axis is a key regulator, other pathways also contribute to the dysregulated autophagy and fibrosis in AF. The IL-33/ST2 signaling is crucial in AF-induced atrial fibrosis, likely through regulating autophagy to promote fibroblast activation and inflammation. ST2 knockdown reduces inflammation, fibrosis, and autophagy, providing insights into potential therapeutic targets for AF-related atrial fibrosis.