Abstract
The role of microRNA-214-3p (miR-214-3p) in cardiac fibrosis was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced cardiac fibrosis. MiR-214-3p was markedly decreased in the fibrotic myocardium of a mouse Ang-II infusion model, but was upregulated in Ang-II-treated mouse myofibroblasts. Cardiac fibrosis was shown attenuated in Ang-II-infused mice received tail vein injection of miR-214-3p agomir. Consistently, miR-214-3p inhibited the expression of Col1a1 and Col3a1 in mouse myofibroblasts in vitro. MiR-214-3p could bind the 3′-UTRs of enhancer of zeste homolog 1 (EZH1) and −2, and suppressed EZH1 and −2 expressions at the transcriptional level. Functionally, miR-214-3p mimic, in parallel to EZH1 siRNA and EZH2 siRNA, could enhance peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and inhibited the expression of Col1a1 and Col3a1 in myofibroblasts. In addition, enforced expression of EZH1 and −2, and knockdown of PPAR-γ resulted in the increase of Col1a1 and Col3a1 in myofibroblasts. Moreover, the NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in myofibroblasts. Taken together, our results revealed that EZH1 and −2 were novel targets of miR-214-3p, and miR-214-3p might be one potential miRNA for the prevention of cardiac fibrosis.
Highlights
Cardiac fibrosis participates in many cardiac pathophysiologic processes, with the characterizations of proliferation of cardiac fibroblasts and excessive accumulation of extracellular matrix in myocardium [1]
Masson staining results revealed that the perivascular fibrosis was significantly increased in the myocardium of a mouse angiotensin II (Ang-II) infusion model (p < 0.01) (Figure 1C)
RT-qPCR results indicated that miR-21 was upregulated, but miR-1, -133b, -16 and -214-3p were downregulated in Ang-II-induced mouse myocardium (p < 0.05, p < 0.01, respectively) (Figure 1E)
Summary
Cardiac fibrosis participates in many cardiac pathophysiologic processes, with the characterizations of proliferation of cardiac fibroblasts and excessive accumulation of extracellular matrix in myocardium [1]. The initial reparative fibrosis is crucial for preventing rupture of the ventricular wall, the exaggerated fibrotic response contributes to progressive impairment of cardiac function, heart failure, fatal arrhythmia and sudden cardiac arrest [2]. Cardiac fibroblasts are the most prevalent cell type in the heart, upon injury and the stimulations of fibrogenic mediators, these cells transform to more active myofibroblast phenotype. Myofibroblasts are the main effector cells in cardiac fibrosis, which express contractile proteins and exhibit migratory, proliferative and secretory properties [3]. No efficient therapeutic approach is available for inhibiting cardiac fibrosis. Understanding the mechanisms responsible for cardiac fibrosis is crucial to set up antifibrotic therapy strategies for patients with heart diseases
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