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
Integrative Physiology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
bioRxiv. 2025 Jun 7:2025.06.07.658396. doi: 10.1101/2025.06.07.658396.
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.
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 ().
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.
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.
儿童特发性扩张型心肌病（iDCM）是一种危及生命的疾病。人们对其细胞和转录格局知之甚少，且缺乏疾病特异性动物模型限制了我们对其机制的理解。我们之前证明，小儿iDCM血清循环蛋白可促进病理重塑，且分泌型卷曲相关蛋白1（sFRP1）可增加心肌细胞的僵硬度。在此，我们研究了sFRP1导致心脏功能障碍的机制。
在新生大鼠心室肌细胞中评估sFRP1与异丙肾上腺素（ISO）联合使用的效果（以重现小儿扩张型心肌病患者中观察到的循环儿茶酚胺增加），并通过腹腔注射在新生大鼠中进行评估。分别通过超声心动图和下一代测序研究功能和分子机制。通过蛋白质印迹法测定蛋白质水平和定位。通过原子力显微镜测量组织僵硬度。将数据与离体人类心脏组织进行比较。
我们发现ISO + sFRP1可重新激活胎儿基因程序并促进心脏功能障碍、扩张和僵硬度增加。重要的是，我们发现小儿iDCM心脏的僵硬度也增加。我们在ISO + sFRP1处理的大鼠和小儿iDCM心脏中均发现Notch和WNT信号通路的共同激活。从机制上讲，抑制Notch或β-连环蛋白可预防病理重塑，并且抑制Notch可改善ISO + sFRP1处理的大鼠和新生大鼠心室肌细胞的心脏功能并减少心室扩张。
我们在小儿iDCM心脏和我们的ISO + sFRP1处理的大鼠中发现Notch和WNT信号通路存在一致的改变。抑制Notch可消除病理变化。这些发现为小儿iDCM提供了新的机制见解和潜在的治疗靶点。
