Inhibitory effects of propylene glycol alginate sodium sulfate derivatives on atrial fibrosis in atrial fibrillation

[Display omitted] Atrial fibrosis is the hallmark of structural remodeling in the pathogenesis of atrial fibrillation (AF). Meanwhile, AF causes a hypercoagulable state, and then provokes pro-fibrotic response. To discover a potential effective AF treatment targeting both coagulation and atrial fibrosis, this study investigated the structure–activity relationship of propylene glycol alginate sodium sulfate (PSS) derivatives with heparin-like activity on TGF-β1-induced atrial fibrosis. We found that PSS derivatives had significantly inhibitory effects on proliferation, migration, phenotypic transformation, and secretion/deposition of extracellular matrix of atrial fibroblasts. Among them, PGGS showed the optimal anti-atrial fibrotic activity by suppressing TGF-β1-induced activation of Smad2/3 signaling pathway. Furthermore, the study in vivo indicated that PGGS treatment displayed a reduced atrial fibrosis and AF inducibility, and attenuated the hypercoagulable state by decreasing D-dimer level and thrombin (FIIa) activity in MHC-TGF-β1 cys33ser transgenic mice, which had increased fibrosis in atrium but not in the ventricles. Our results demonstrated that PSS derivatives, especially PGGS, were potential anti-atrial fibrosis and anti-coagulant agents for AF prevention. Our study is beneficial in extending the current understandings of the function of PSS on atrial fibrosis and vulnerability to AF.