Global MicroRNA Profiling of the Mouse Ventricles during Development of Severe Hypertrophic Cardiomyopathy and Heart Failure

Abstract

MicroRNAs (miRNAs) regulate post-transcriptional gene expression during development and disease. We have determined the miRNA expression levels of early- and end-stage hypertrophic cardiomyopathy (HCM) in a severe, transgenic mouse model of the disease. Five miRNAs were differentially expressed at an early stage of HCM development. Time-course analysis revealed that decreased expression of miR-1 and miR-133a commences at a pre-disease stage, and precedes upregulation of target genes causal of cardiac hypertrophy and extracellular matrix remodelling, suggesting a role for miR-1 and miR-133a in early disease development. At end-stage HCM, 16 miRNA are dysregulated to form an expression profile resembling that of other forms of cardiac hypertrophy, suggesting common responses. Analysis of the mRNA transcriptome revealed that miRNAs potentially target 15.7% upregulated and 4.8% downregulated mRNAs at end-stage HCM, and regulate mRNAs associated with cardiac hypertrophy and electrophysiology, calcium signalling, fibrosis, and the TGF-β signalling pathway. Collectively, these results define the miRNA expression signatures during development and progression of severe HCM and highlight critical miRNA regulated gene networks that are involved in disease pathogenesis.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

“…miRNAs are known regulators of many genes and physiologic processes including cardiac hypertrophy and fibrosis (51,52). Studies of miRNA profiling in HCM patients and transgenic mouse models have identified patterns that are unique to each HCM mutation (53)(54)(55)(56), but it is unknown when in the disease process these differences are present. High-throughput sequencing of miRNAs (miRNA-seq) in the young mutant mice and littermate controls ( Figure 5 and Supplemental Tables 6 and 7) revealed no difference (none showed >2-fold difference) in miRNA expression between the 2 controls (control-M and control-T), as expected (Figure 5A).…”

MicroRNA regulators of cholinergic signaling link neuromuscular, cardiac and metabolic systems

“…The cMLCK kinase phosphorylates regulatory light chains in the heart, and a decrease in RLC phosphorylation has been shown to promote myocyte hypertrophy in vivo (44). MiR-1 is also dysregulated in mouse ventricles during development of severe hypertrophic cardiomyopathy and heart failure (45). Thus, accurate miR-1 levels are important for correct cardiac functioning.…”

Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

“…Finally, cardiac hypertrophy may associate with the activation of Nppa, Nppb, and Acta1 (skeletal α-actin) fetal gene program [72] . It has deemed that the key components of cardiomyocyte hypertrophy mediator might be miRNA-dependent regulator of calcium signaling pathways [73] . Whether altered signature of miRNA is considered a clue for cardiac hypertrophy and dysfunction, low number of direct clinical evidence regarding specifically HF phenotypes' development relating to miRNA signature remains a part of scientific discussion [59] .…”