bioRxiv : the preprint server for biology · 2025
A novel Notch and WNT signaling mechanism contribute to paediatric DCM: a pathway to new therapeutics.
СтатьяПрепринтНазвание и аннотация: Перевод пока не подготовлен
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Nyarko Obed O, Rausch Ethan, Goff Jared R H, Karimpour-Fard Anis, Conard Caitlyn S, Hernandez-Lagunas Laura, Burns McKenna P A, Peña Brisa, Miyamoto Shelley D, Stauffer Brian L, Sucharov Carmen C
Аннотация
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.
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.