Abstract 11625: Role of Wnts and Secreted Frizzled-Related Protein-1 in Atrial Fibroblast Pathophysiology During Atrial Fibrotic Remodeling
Introduction: Left atrial (LA) fibroblasts (FBs) respond differentially vs left ventricular (LV) to fibrotic stimuli underlying LA selective fibrosis and atrial fibrillation (AF) in contexts like heart failure (HF). The most differentially expressed gene between LA and LV FBs (28 fold greater in LA) is secreted frizzled-related protein-1 (sFRP1), an endogenous Wnt antagonist. However, the role of sFRP1 and Wnt signaling in FB pathophysiology is unknown.
Methods: HF-related LA remodeling was induced in dogs by ventricular tachypacing (VTP 240 bpm). mRNA and protein were quantified in freshly isolated FBs by qPCR (19 Wnt ligands) and immunoblot. Recombinant Wnt and sFRP1 proteins were used to assess effects on FBs; lentivirus-transferred small interfering RNA (siRNA) to knock down sFRP1.
Results: AF duration, collagen1 and fibronectin expression increased at 1 and 2 wk VTP, paralleling LA fibrosis. Wnt2 and Wnt5a showed high FB expression. Wnt2 increased in LA FBs at 2 wks (4.8 fold) but did not change in LV (Fig A). Wnt5a decreased quickly in LA and LV (at 12 hrs, -8.9 and -2.9 fold) and remained decreased in LA up to 2 wks (Fig B). sFRP1 decreased at 12 and 24 hrs (-3.9 and -5.4 fold). Treatment of LA FBs with Wnt2 or Wnt5a increased cell size, collagen1 (1.7 and 1.8 fold) and fibronectin (31 and 2.1 fold) expression, and decreased sFRP1 mRNA (by 95% and 54%) (Fig C). Recombinant sFRP1 decreased fibronectin expression (-2.4 fold). Moreover, sFRP1 KD (85% reduction) increased Wnt2 and Wnt5a expression by 4.1 and 7.5 fold (Fig D), suggesting mutual negative interaction between sFRP1 and Wnt signaling in regulating ECM protein secretion.
Conclusions: A variety of Wnt ligands are strongly and dynamically expressed in LA. Wnt2 and Wnt5a show countervailing changes during LA fibrosis development in HF, and negatively interact with sFRP1. Our results indicate complex regulation of atrial FB function by the Wnt system, which may provide novel therapeutic targets for AF-substrate prevention.
Author Disclosures: S. Surinkaew: None. K. Dawson: None. X.Y. Qi: None. Y. Sun: None. H. Huang: None. Y. Chen: None. P. Naud: None. S. Nattel: None.
- © 2015 by American Heart Association, Inc.