Abstract
Cardiac fibrosis is the pathological consequence of fibroblast proliferation and fibroblast-to-myofibroblast transition. As a new class of endogenous non-coding RNAs, circular RNAs (circRNAs) have been identified in many cardiovascular diseases including fibrosis, generally acting as microRNA (miRNA) sponges. Here, we report that the expression of circRNA–circNFIB was decreased in mice post-myocardial infarction heart samples, as well as in primary adult cardiac fibroblasts treated with TGF-β. Forced expression of circNFIB decreased cell proliferation in both NIH/3T3 cells and primary adult fibroblasts as evidenced by EdU incorporation. Conversely, inhibition of circNFIB promoted adult fibroblast proliferation. Furthermore, circNFIB was identified as a miR-433 endogenous sponge. Overexpression of circNFIB could attenuate pro-proliferative effects induced by the miR-433 mimic while inhibition of circNFIB exhibited opposite results. Finally, upregulation of circNFIB also reversed the expression levels of target genes and downstream signaling pathways of miR-433. In conclusion, circNFIB is critical for protection against cardiac fibrosis. The circNFIB–miR-433 axis may represent a novel therapeutic approach for treatment of fibrotic diseases.
Highlights
Cardiac fibrosis, defined as the imbalance of extracellular matrix (ECM) production and degradation, which contributes to accumulation of connective tissue proteins in the interstitial and perivascular tissues, plays a crucial role in the development and evolution of heart failure (Weber et al, 2013)
To further confirm which circRNA is involved in cardiac fibrosis, we explored the expression levels of these three circRNAs in heart samples from the 3-week post-myocardial infarction (MI) model
These findings indicate a strong connection between the expression of circNFIB and cardiac fibrosis both in vivo and in vitro
Summary
Cardiac fibrosis, defined as the imbalance of extracellular matrix (ECM) production and degradation, which contributes to accumulation of connective tissue proteins in the interstitial and perivascular tissues, plays a crucial role in the development and evolution of heart failure (Weber et al, 2013). Fibrosis is a common pathological feature of most adverse ventricular remodeling, such as myocardial infarction (MI), diabetic cardiomyopathy, hypertrophic, and dilated cardiomyopathy (DCM) (Gyongyosi et al, 2017). It normally includes three overlapping phases: proliferation, granulation, and maturation. The transformation involves subcellular changes such as increased expression of α-smooth muscle actin circNFIB/miR-433 Axis Regulates Fibroblast Proliferation (α-SMA) and secretion of extracellular procollagen chains into collagen type I and type III fibrils (Li et al, 2014; Watson et al, 2014; Gyongyosi et al, 2017). The accumulation of excessive diffused collagen results in disruption of myocardial architecture, myofibrils disarray, and mechanical, electrical, and vasomotor dysfunction (Segura et al, 2014)
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