A novel Notch and WNT signaling mechanism contribute to pediatric DCM: a pathway to new therapeutics
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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 respectively. 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.
Clinical perspective
What is new?
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iDCM in children continues to be poorly understood due to the lack of an animal model and lack of understanding of the disease mechanisms.
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This study establishes a unique young rat model that recapitulates key features of the disease, which include impaired systolic function with ventricular dilation, myocardial stiffness and distinct transcriptomic signatures.
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This study investigates molecular pathways commonly altered in pediatric iDCM heart and our novel animal model.
What are the clinical implications
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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, suggesting targeting the Notch pathway may be a viable option to treat pediatric DCM.
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These findings provide a preclinical model to investigate targeted interventions for pediatric DCM.
