Abstract
The action of β-adrenergic receptors (β-ARs) induces cardiac fibroblast (CF) proliferation and collagen synthesis and is a major source of the cardiac fibrosis caused by various diseases. Recently, microRNA-214 (miR-214) was found to play an important role in the pathogenesis of cardiac remodelling. In the present study, we examined the role and the underlying mechanism of miR-214 in isoproterenol (ISO, a β-AR agonist)-induced CF proliferation and collagen synthesis. The expression of miR-214 was increased in both ISO-mediated fibrotic heart tissue and fibroblasts. Downregulation of miR-214 by antagonists attenuated the proliferation and collagen synthesis in ISO-treated CFs. Using bioinformatics analysis and luciferase assays, mitofusin2 (Mfn2), a critical regulator of cell proliferation and tissue fibrosis, was identified as a direct target gene of miR-214; this result was confirmed by western blot analysis. Additionally, corresponding to the upregulation of miR-214, the expression of Mfn2 was downregulated in the fibrotic heart and fibroblasts. Furthermore, the downregulation of miR-214 inhibited the activation of ERK1/2 MAPK signalling induced by ISO treatment. In conclusion, our study demonstrated that miR-214 mediates CF proliferation and collagen synthesis via inhibition of Mfn2 and activation of ERK1/2 MAPK signalling, which provides a new explanation for the mechanism of β-AR activation-induced cardiac fibrosis.
Highlights
Cardiac fibrosis is an important pathological change occurring in cardiac remodelling following ischemic heart disease, hypertension, cardiomyopathy, and other diseases
Our results show that miR-214 mediates ISO-induced proliferation and collagen synthesis in cardiac fibroblast (CF) by directly targeting Mfn[2] and activating the downstream extracellular signal-regulated kinase– mitogen-activated protein kinase (ERK1/2 MAPK) signalling pathway
We found that miR-214 was significantly upregulated in a cardiac fibrosis model induced by ISO, a β -adrenergic receptors (β -ARs) agonist
Summary
Cardiac fibrosis is an important pathological change occurring in cardiac remodelling following ischemic heart disease, hypertension, cardiomyopathy, and other diseases. Recent studies have reported that downregulation of miR-214 can attenuate unilateral ureteral obstruction (UUO)-induced renal fibrosis[19]. These studies suggest that miR-214 may play an important role in cardiac fibrosis induced by excessive stimulation of β -ARs. In the present study, we explored the role and mechanism of miR-214 in isoproterenol (ISO, a β -AR agonist)-induced cardiac fibrosis. Our results show that miR-214 mediates ISO-induced proliferation and collagen synthesis in CFs by directly targeting Mfn[2] and activating the downstream extracellular signal-regulated kinase– mitogen-activated protein kinase (ERK1/2 MAPK) signalling pathway
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