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Ventricular remodeling after myocardial infarction (MI) is the prominent cause of heart failure. Previous studies confirmed that the macrophage activation post-MI affects the remodeling of ventricle. We hypothesized that there is a certain miRNA regulating inflammatory factor that is involved in the ventricular remodeling. In this study we probed the mechanisms of the miR-155 in monocyte-macrophages on ventricular remodeling after MI.
MiR-155 knockin (miR-155+/+) and knockout (miR-155-/-) mice were obtained by bone marrow transplantation in wild-type (WT) C57BL/6J mice. MI model was established by ligation of the left anterior descending coronary artery. Parameters were evaluated after 1, 7, and 14 days post-MI. Cardiac color ultrasonic detection was employed to assess left ventricular ejection fraction (LVEF). HE staining and Masson trichromatic staining were performed to evaluate the cell volume and fibrosis of myocardium, while galectin-3 expression was visualized by using immunohistochemistry. The expression of miR-155 and SOCS1 mRNA was detected by using qRT-PCR, ELISA and Western blot were used for measurement of protein expression. Additionally, primary cultured macrophages were studied in vitro and SOCS1 siRNA was applied to explore the involvement of SOCS1.
MiR-155 KI resulted in impaired LVEF compared to WT group, and miR-155 KO did not exert significant effect. Histological staining showed that the myocardial cell volume and fibrosis degree were enhanced by miR-155 KI. Positive staining of galectin-3 in the macrophages was increased in miR-155 KI and was decreased in miR-155 KO, compared to that in WT. The expression of miR-155 was unchanged in myocardial cells but increased in macrophages after MI for up to 14 days in the WT group. Compared to that in WT, elevated TNF-α and decreased IL-10 levels were observed in the plasma and myocardium in KI group, whereas that in KO group were reversed.
To verify if SOCS1 is responsible for the regulatory effects of miR-155, the in vitro experiments were performed by using primary cultured macrophages. TNF-α was increased and IL-10 was decreased by miR-155 KI in macrophages compared to that of WT in vitro, and reversed by miR-155 KO. The mRNA and protein expressions of SOCS1 were augmented by miR-155 knockdown, and were suppressed by miR-155 overexpression. Furthermore, deletion of SOCS1 by siRNA resulted in augmented TNF-α and suppressed IL-10.
In conclusion, our results suggested that miR-155 accounts for the impairment of cardiac function and ventricular remodeling after MI, and such effects could be associated with SOCS1-mediated inflammatory process.