Abstract 4353779: A novel Notch and WNT signaling mechanism contribute to pediatric DCM: a pathway to new therapeutics

Background: Idiopathic dilated cardiomyopathy (iDCM) in children is a life-threatening disease. Little is known about its cellular and transcriptional landscape, and the lack of disease-specific animal models limits our understanding of its mechanisms. We previously demonstrated that pediatric iDCM serum-circulating proteins promote pathologic remodeling in vitro , and that secreted frizzled related protein 1 (sFRP1) increases stiffness in cardiomyocytes. Here we investigated the mechanisms by which sFRP1 contributes to cardiac dysfunction. Methods: The effect of sFRP1 in combination with isoproterenol (ISO) (to recapitulate the increase in circulating catecholamine observed in pediatric DCM patients) was evaluated in neonatal rat ventricular myocytes ( in vitro ), and in neonatal rats through intraperitoneal injections ( in vivo ). Function and molecular mechanisms were investigated through echocardiography and next-generation-sequencing. Protein levels and localization were determined by Western blot. Tissue stiffness was measured by Atomic Force Microscopy. In vitro and in vivo data were compared to explanted human heart tissue ( ex vivo ). Results: We show that ISO+sFRP1 reactivates the fetal gene program in vitro, and promotes cardiac dysfunction, dilation and stiffness in vivo . Importantly, we show stiffness is also increased in pediatric iDCM hearts. We identified co-activation of Notch and WNT signaling in both ISO+sFRP1-treated rats and pediatric iDCM hearts. Mechanistically, in vitro inhibition of Notch or β-catenin prevented pathological remodeling, and Notch inhibition improved cardiac function and reduced ventricular dilation in ISO+sFRP1-treated rats and NRVMs. Conclusion: We identified concordant alterations in Notch and WNT signaling in pediatric iDCM hearts and in our ISO+sFRP1-treated rats. Notch inhibition abrogated pathologic changes in vitro and in vivo . These findings provide novel mechanistic insights and a potential therapeutic target for pediatric iDCM.