A novel Notch and WNT signaling mechanism contribute to paediatric DCM: a pathway to new therapeutics
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Background
Paediatric Idiopathic dilated cardiomyopathy (iDCM) is a life-threatening disease. The lack of disease-specific animal models limits our understanding of its mechanisms. We previously demonstrated that paediatric 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 iDCM.
Methods
The effect of sFRP1 in combination with isoproterenol (ISO) (to recapitulate the increase in circulating catecholamine observed in paediatric iDCM) 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.
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 paediatric iDCM hearts. We identified co-activation of Notch and WNT signaling in both ISO+sFRP1-treated rats and paediatric iDCM hearts. Mechanistically, in vitro inhibition of Notch or β-catenin prevented pathological remodeling, and Notch inhibition improved cardiac function, myocardial stiffness and ventricular dilation in ISO+sFRP1-treated rats.
Conclusion
We identified alterations in Notch and WNT signaling in paediatric iDCM hearts and in our model. Notch inhibition abrogated pathologic changes in vitro and in vivo . These findings provide novel mechanistic insights and a potential therapeutic target for paediatric iDCM.
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Key Question- Age-specific disease mechanisms may explain the heterogenous response of paediatric iDCM patients to standard heart failure therapies that are effective in adults.
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Key Finding- This study identifies Notch and WNT as important pathways altered in paediatric DCM. Additionally, it establishes a unique young rat model of the disease that recapitulates important aspects of paediatric iDCM, including an increase in cardiac stiffness.
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Take-home Message- This study uncovers a potential therapeutic target of paediatric DCM via Notch inhibition.
Translational perspective
Idiopathic dilated cardiomyopathy (iDCM) in children continues to be poorly understood. This study investigates molecular pathways altered in paediatric iDCM and establishes a unique young rat model that recapitulates key features of the disease. These features include impaired systolic function with ventricular dilation, myocardial stiffness and distinct transcriptomic signatures. We identified Notch and WNT co-activation as key regulators of pathological remodeling and cardiac dysfunction and show that inhibition of Notch signaling can prevent pathological remodeling and cardiac dysfunction. These findings provide a preclinical model to investigate targeted interventions for paediatric iDCM.
