Differences in microRNA-29 and Pro-fibrotic Gene Expression in Mouse and Human Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy and fibrosis. Studies in two mouse models (R92W-TnT/R403Q-MyHC) at early HCM stage revealed upregulation of endothelin (ET1) signaling in both mutants, but TGFβ signaling only in TnT mutants. Dysregulation of miR-29 expression has been implicated in cardiac fibrosis. But it is unknown whether expression of miR-29a/b/c and profibrotic genes is commonly regulated in mouse and human HCM. Conclusions: Our in vitro studies suggest that activation of ET1 signaling in cardiac myocytes increases reactive oxygen species and stimulates TGFβ secretion, which downregulates miR-29a and increases collagen in fibroblasts, thus contributing to fibrosis. Our gene expression studies in mouse and human HCM reveal allele-specific differences in miR-29 family/profibrotic gene expression in mouse HCM, and activation of anti-hypertrophic/anti-fibrotic genes and pathways in human HCM.

Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy

“…Human HCM: We analyzed publicly available microarray data from 107 patients and 39 healthy controls 12 , 27 . Genotype and phentype date was obtained from the publicly available Master thesis by Virginia Hebl.…”

“…3 f). In a prior study, we performed principle component analysis (PCA) of the mRNA data and showed clustering of HCM patient data, as well as good separation of patients from healthy controls in component 2 (Y-axis) of the PCA plot 27 .…”

Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes

“…This finding limits the specificity of JAK2 to the pathogenesis of HCM fibrosis, but also supports the fundamental finding that PPI network edges more so than specific nodes are important for defining pathobiological differences between a cohort of patients with the same disease (i.e., HCM). Nonetheless, we recognize that alternative mechanisms to JAK2-STAT3 are anticipated to regulate HCM fibrosis, which may include established pathways, such as endothelin-1 and transforming growth factor (TGF)-β signaling, in particular 38 , as 17 of 18 (94%) of the HCM PPIs networks included one of these intermediaries. Similarly, targets beyond COL4A2, such as WWP2, shown previously to regulate cardiac fibrosis 39 and identified in all 18 HCM patient networks, are anticipated to regulate HCM fibrosis.…”

N-acetyl Cysteine Can Blunt Metabolic and Cardiovascular Effects via Down-regulation of Cardiotrophin-1 in Rat Model of Fructose-induced Metabolic Syndrome

“…In addition, Wu et al [69] demonstrated that NAC treatment could prevent pyroptosis which is a cellular mechanism for the pro-atherosclerotic plaque formation in human aortic endothelial cells. Furthermore, mouse and human hypertrophic cardiomyopathy were antagonized by NAC treatment through stimulation of miR-29a expression and suppression of pro-brotic gene TGFβ expression and secretion [70]. Also, it has been demonstrated that NAC could inhibit the decrease in collagen I/III ratio which play a role in cardiac extracellular matrix composition and cardiac hypertrophy [71].…”