Abstract 4367525: Inhibition of PDE10A Attenuates Pressure Overload-induced Right Ventricular Dysfunction via Modulation of Calcium Signaling and β-Catenin Pathways

Abstract

Introduction: Right ventricular (RV) dysfunction is an independent predictor of poor outcomes in heart failure. However, the molecular mechanisms of RV remodeling remain unclear. Phosphodiesterase 10A (PDE10A), degrading cAMP and cGMP, is involved in β-catenin signaling in cancer and neurodegenerative diseases. While β-catenin and calcium signaling contribute to left ventricular remodeling, the role of PDE10A in RV dysfunction is unknown. Methods and Results: PDE10A expression was significantly upregulated in the RV myocardium from patients with severe RV dysfunction compared to patients with preserved RV function (p=0.0005). PDE10A knockout (KO) mice and their wild-type (WT) littermates underwent pulmonary artery banding (PAB) or sham surgery (n=6-8 per group). Five weeks after surgery, PAB induced 2-fold dilatation of RV dimension (p=0.002) and reduction of tricuspid annular peak systolic velocity (RV-s') and tricuspid annular plane systolic excursion (TAPSE) (p<0.0001 for both) by echocardiography. Right ventricular systolic pressure (RVSP) was significantly elevated in the PAB group (p<0.0001). Western blot analysis revealed the PAB-induced upregulation of PDE10A in the RV myocardium in WT mice (p=0.0016). In contrast, PDE10A KO mice showed preserved RV geometry and function even after PAB compared to WT mice (improved TAPSE and RV-s’, p<0.05 for both). Western blot analysis of RV myocardial tissue revealed that the PAB-triggered upregulation of hypertrophy markers such as phospho-ERK and phospho-CaMKII, calcium signaling-related channel such as TRPV2, pro-apoptotic markers such as Bax/Bcl2 ratio and cleaved caspase 3, and active β-catenin was attenuated in PDE10A KO mice compared to WT mice. Pressure-volume loop study confirmed the improvement of RV contractility (Ees) and RV-PA coupling (Ees/Ea) in PDE10A KO mice. In a second experiment, C57BL/6J wild-type mice received the selective PDE10A inhibitor MT3014 (5 mg/kg/day) or vehicle after PAB (n=10 each). PDE10A inhibition improved RV function and hypertrophy, with reduced expression of phospho-ERK, α-SMA, phospho-NF-κB, active β-catenin, and TRPV2 (p<0.05). These findings suggest PDE10A contributes to RV dysfunction via TRPV2-mediated calcium and β-catenin signaling. Conclusions: Genetic deletion or chronic pharmacologic inhibition of PDE10A attenuates RV remodeling and dysfunction by modulating calcium signaling and β-catenin pathways. PDE10A is a promising therapeutic target for RV failure.