Abstract
Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and main indication for heart transplantation in children. Therapies specific to pediatric DCM remain limited due to lack of a disease model. Our previous study showed that treatment of neonatal rat ventricular myocytes (NRVMs) with serum from nonfailing or DCM pediatric patients activates the fetal gene program (FGP). Here we show that serum treatment with proteinase K prevents activation of the FGP, whereas RNase treatment exacerbates it, suggesting that circulating proteins, but not circulating miRNAs, promote these pathological changes. Evaluation of the protein secretome showed that midkine (MDK) is upregulated in DCM serum, and NRVM treatment with MDK activates the FGP. Changes in gene expression in serum-treated NRVMs, evaluated by next-generation RNA-Seq, indicated extracellular matrix remodeling and focal adhesion pathways were upregulated in pediatric DCM serum and in DCM serum–treated NRVMs, suggesting alterations in cellular stiffness. Cellular stiffness was evaluated by Atomic Force Microscopy, which showed an increase in stiffness in DCM serum–treated NRVMs. Of the proteins increased in DCM sera, secreted frizzled-related protein 1 (sFRP1) was a potential candidate for the increase in cellular stiffness, and sFRP1 treatment of NRVMs recapitulated the increase in cellular stiffness observed in response to DCM serum treatment. Our results show that serum circulating proteins promoted pathological changes in gene expression and cellular stiffness, and circulating miRNAs were protective against pathological changes.
Highlights
Heart failure (HF) is a major public health issue in the United States and a leading cause of hospitalization in both adult and pediatric populations [1]
dilated cardiomyopathy (DCM) is present in both adult and pediatric populations, we and others have identified age-specific differences, including changes in β-adrenergic receptor (β-AR) density, a unique transcriptome profile, lack of cardiomyocyte hypertrophy, and minimal interstitial fibrosis in the pediatric population when compared with adults [4,5,6,7]
To further explore pathological remodeling associated with pediatric DCM, we evaluated gene expression changes in NF serum– and DCM serum–treated neonatal rat ventricular myocytes (NRVMs)
Summary
Heart failure (HF) is a major public health issue in the United States and a leading cause of hospitalization in both adult and pediatric populations [1]. DCM is present in both adult and pediatric populations, we and others have identified age-specific differences, including changes in β-adrenergic receptor (β-AR) density, a unique transcriptome profile, lack of cardiomyocyte hypertrophy, and minimal interstitial fibrosis in the pediatric population when compared with adults [4,5,6,7]. There is minimal fibrosis, extracellular matrix (ECM) remodeling is present in the pediatric DCM heart [5, 8]. Stiffness in adults with HF has been extensively studied, less is known about the contribution of stiffness to HF in the pediatric population [10]
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