Abstract 18958: Changes in Wnt-Frizzled System in Heart Failure and Associated AF Substrate

Abstract

Introduction: The wnt-frizzled (Fzd) signaling cascade, important in development, has recently been implicated in post myocardial infarction scar formation. Fzd receptors (Fzd1-6) interact with wnt ligands to produce downstream effects antagonized by the endogenous antagonist sFRP. This study examined the potential role of wnt-Fzd signaling in heart failure (HF), in which atrial-selective extracellular matrix (ECM) remodeling creates a substrate for AF. Methods: HF was induced by ventricular tachypacing (VTP 240 bpm) in dogs. Time-dependent changes were studied with VTP ×12 hr, 24 hr, 1 wk or 2 wks. mRNA was measured in freshly isolated left atrial (LA) and ventricular (LV) fibroblasts (qPCR). Results: Fzd1 expression was LA selective (16.6 × LV*, P<0.05) but did not change with VTP. Fzd2 increased in LA at 1 wk (15 fold***, ***P<0.001) and 2 wks (13 fold***), increasing less in LV (3.7 fold* at 2 wk). Fzd3 and Fz5 did not change. Fzd4 decreased quickly in LA (12 hr, -5.3 fold**, **P<0.01; 24 hr, -7.6 fold**) and then returned to control. Fzd6 increased slightly in LA at 2 wk (2.9 fold*). Agonists of the pathway, wnt3a and wnt5b, were also investigated. Wnt3a was undetectable in LA or LV fibroblasts. Wnt5b decreased in LA at 12 hr (-4.3 fold**) and 24 hr (-4.25 fold**). LV wnt5b expression decreased later and to a lesser extent: 24 hr (-1.72 fold*) and 1 wk (-1.75*). The endogenous antagonist sFRP1 was expressed selectively in LA (5.5 × LV*). LA levels fell early (-4.8 fold at 12 hr VTP**), remained decreased at 1 wk (-2.2 fold*) and returned to control at 2 wk. Treatment of LA fibroblasts with recombinant sFRP1 (2.5 µg/mL) decreased fibronectin expression (-2.4 fold***), suggesting that sFRP interaction with endogenous wnt-Fzd signaling negatively regulates fibronectin, an important ECM and fibroblast interaction regulator. Fibronectin was upregulated in VTP, with significant changes noted at 24 hrs. Collagen1-α1 was unaffected by sFRP1. Conclusions: The wnt-Fzd system is altered in HF, with the most prominent changes occurring in LA, consistent with LA-selective ECM remodeling. Downregulation of sFRP1 may contribute to rapid increases in LA fibronectin expression with VTP/HF, thereby playing an important pathophysiological role in AF-promoting ECM remodeling.