Abstract 14585: Early Right Ventricular Snail Expression is a Druggable Target to Improve Right Ventricular Function in Pressure-Overloaded Right Heart Failure

Abstract

Introduction: Cardiac fibrosis disrupts the myocardial architecture, impairs the exchange of oxygen and nutrients, and puts the heart at risk of failure. Snail (SNAI1) is a transcriptional factor involved in cell plasticity that has been linked to fibroblast-to-myofibroblast transition (FMT) in the hypoxic heart, however, it is unknown whether inhibition of FMT reduces fibrosis and improves right ventricular (RV) function in the pressure overloaded RV. We hypothesized that Snail is necessary for FMT and, as BMP signaling inhibits Snail, that two BMPR2 activators, FK506 and Enzastaurin, reduce cardiac fibrosis and improve cardiac function in a pulmonary artery banding (PAB) mouse model. Methods and Results: We performed PAB surgery on snail-YFP reporter mice and observed transient Snail expression exclusively in the RV 3-7 days after inducing pressure overload (Fig. 1). In PeriostinCre-TdTomato reporter mice we showed that Snail was expressed in proliferating Periostin and vimentin positive fibroblasts representing activated myofibroblasts. In vitro , stimulation of cardiac fibroblasts with TGFbeta resulted in the early expression of Snail at 2 hours, followed by a Snail-dependent Acta2 expression after 24 hours and Col1 after 48 hours, suggesting the critical role of Snail in fibroblast activation. Furthermore, application of stretch and pressure (50kPa) to cardiac fibroblasts, mimicking pressure-overload in vivo , increased Snail expression. FK506 and Enzastaurin inhibited Tgf-b induced Snail expression in vitro as well as in vivo when administered immediately after PAB surgery (Fig. 2). Finally, long-term treatment with Enzastaurin resulted in preserved RV function at week 7 as assessed by cardiac MRI (Fig. 3, N=6). Conclusions: Snail expression is strongly associated with fibroblast activation in the pressure-overloaded RV. Inhibiting Snail with BMPR2 pathway modulators is a promising approach to improve RV function in the pressure-overloaded RV.