Abstract
Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. The wide spread of high-throughput sequencing casts doubt on its monogenic nature, suggesting the presence of mechanisms of HCM development independent from mutations in sarcomeric genes. From this point of view, HCM may arise from the interactions of several HCM-associated genes, and from disturbance of regulation of their expression. We developed a bioinformatic workflow to study the involvement of signaling pathways in HCM development through analyzing data on human heart-specific gene expression, miRNA-target gene interactions, and protein–protein interactions, available in open databases. Genes regulated by a pool of miRNAs contributing to human cardiac hypertrophy, namely hsa-miR-1-3p, hsa-miR-19b-3p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-93-5p, hsa-miR-133a-3p, hsa-miR-155-5p, hsa-miR-199a-3p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-451a, and hsa-miR-497-5p, were considered. As a result, we pinpointed a module of TGFβ-mediated SMAD signaling pathways, enriched by targets of the selected miRNAs, that may contribute to the cardiac remodeling in HCM. We suggest that the developed network-based approach could be useful in providing a more accurate glimpse on pathological processes in the disease pathogenesis.
Highlights
Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease, with an estimated prevalence of 1:500–1:200 [1]
MiRNAs are implicated in the fine regulation of a diverse spectrum of physiological processes; miRNAs’ dysregulation is associated with many pathological processes in humans, including hypertrophy, fibrosis, and apoptosis of myocardial cells [6,7]. miRNAs have been shown to be involved in the development of various cardiovascular diseases, such as atherosclerosis, myocardial ischemia, and heart failure
We considered only those targets of selected miRNAs that are expressed in human heart tissue to provide a more accurate glimpse of the pathological processes in the heart muscle involved in HCM
Summary
Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease, with an estimated prevalence of 1:500–1:200 [1]. Modern transcriptomic studies cast doubts on the monogenic nature of the disease, which suggests the presence of sarcomereindependent non-genetic mechanisms of HCM development [2,4,5] From this point of view, HCM may arise from the interactions of several HCM-associated genes, and from a disturbance in the regulation of their expression. To investigate miRNA-mediated signaling pathways in the context of HCM we selected a set of miRNAs based on the data on their contribution to cardiac hypertrophy We considered only those targets of selected miRNAs that are expressed in human heart tissue to provide a more accurate glimpse of the pathological processes in the heart muscle involved in HCM. By using the developed workflow, we identified shared signaling pathways regulated by studied miRNAs that more likely contribute to HCM pathogenesis
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