Circ_0079480 facilitates proliferation, migration and fibrosis of atrial fibroblasts in atrial fibrillation by sponing miR-338-3p to activate the THBS1/TGF-β1/Smad3 signaling

Background: Atrial fibrosis is associated with the pathogenesis of atrial fibrillation (AF). This study aims to discuss the function of circ_0079480 in atrial fibrosis and its underlying mechanism.

Methods: In vitro and in vivo models of atrial fibrosis were established by using angiotensin II (Ang II) to treat human atrial fibroblasts (HAFs) and C57/B6J mice. qRT-PCR and western blot were used to examine the mRNA and protein expression levels. CCK-8, EdU, cell strach, and transwell assays were performed to determine the proliferation and migration of HAFs. Dual-luciferase reporter and RIP/RNA pull-down assays were explored to identify the interaction of miR-338-3p and circ_0079480/THBS1. HE and Masson's trichrome staining experiments were performed to analyze the histopathological change in mice atrial tissues.

Results: Circ_0079480 expression was increased in AF patients' atrial tissues and Ang II-treated HAFs. Silencing circ_0079480 inhibited cell proliferation and migration and reduced fibrosis-associated gene expression in Ang II-treated HAFs. Circ_0079480 could target miR-338-3p to repress its expression. MiR-338-3p inhibitor blocked the inhibitory effects of circ_0079480 knockdown on HAFs proliferation, migration, and fibrosis. Thrombospondin-1 (THBS1) was confirmed as a downstream target of miR-338-3p, and circ_0079480 could Sponge miR-338-3p to upregulate THBS1 expression. Moreover, silencing THBS1 suppressed Ang II-induced proliferation, migration, and fibrosis in HAFs. More importantly, depletion of circ_0079480 inactivated the THBS1/TGF-β1/SMAD3 signaling by upregulating miR-338-3p. Mice experiments also confirmed the suppression of circ_0079480 knockdown on atrial fibrosis.

Conclusion: Circ_0079480 acts as a Sponge of miR-338-3p to upregulate THBS1 expression and activate the TGF-β1/SMAD3 signaling, finally promoting Ang II-induced atrial fibrosis.

Atrial fibrosis; Circ_0079480; TGF-β1/Smad3 signaling; THBS1; miR-338-3p.