Ubiquitin‑proteasomes are the dominant mediators of the regulatory effect of microRNA‑1 on cardiac remodeling after myocardial infarction

Abstract

Patients with ischemic hearts who have refused coronary vascular reconstruction may exhibit dynamic myocardial remodeling and cardiac dysfunction. In the present study, the role of miRNA-1 and its association with the ubiquitin-proteasome system (UPS) in regulating myocardial remodeling was investigated. A myocardial infarction (MI) model was constructed and the hearts were treated with miRNA-1 antagomir, miRNA-1 lentiviral vectors and the UPS proteasome blocker bortezomib. The expression levels of miRNA-1 were evaluated using reverse transcription PCR and the abundance of the ubiquitin-proteasome protein and caspase-3 were evaluated via western blot analysis. Furthermore, the collagen volume fraction was calculated using Masson's trichrome staining, and the apoptosis index was detected via terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling staining. Transforming growth factor (TGF)-β expression was assessed via immunohisto-chemical staining. Echocardiographic characteristics and myocardial infarct size were analyzed. miRNA-1 expression levels were found to be increased following MI. miRNA-1 antagomir administration clearly inhibited miRNA-1 expression, whereas the miRNA-1 lentiviral vector exerted the opposite effect. The levels of 19s proteasome, 20S proteasome and ubiquitin ligase E3 were decreased in the miRNA-1 antagomir group, but were significantly increased in the miRNA-1 lentiviral group; however, only 20S proteasome expression was decreased in the bortezomib group. Collagen hyperplasia and TGF-β expression were decreased in both the miRNA-1 antagomir and bortezomib groups, although the effects of the miRNA-1 antagomir were more noticeable. The miRNA-1 antagomir and the UPS proteasome blocker both alleviated the ultrastructural impairments, demonstrated by a decreased left ventricular (LV) end-diastolic diameter and LV mass, but the miRNA-1 antagomir was also able to increase LV ejection fraction and LV fractional shortening. miRNA-1 regulated UPS-associated mRNA expression and affected the majority of the UPS components in the myocardium, thereby leading to increased myocardial cell apoptosis, myocardial fibrosis and remodeling. The miRNA‑1 antagomir exerted a more prominent cardioprotective effect compared with the UPS proteasome blocker bortezomib.