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 , 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 (), and in neonatal rats through intraperitoneal injections (). Function and molecular mechanisms were investigated through echocardiography and next-generation-sequencing respectively. Protein levels and localization were determined by Western blot. Tissue stiffness was measured by Atomic Force Microscopy. and data were compared to explanted human heart tissue ().

RESULTS

We show that ISO+sFRP1 reactivates the fetal gene program and promotes cardiac dysfunction, dilation and stiffness . 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, 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 and . These findings provide novel mechanistic insights and a potential therapeutic target for pediatric iDCM.