Journal
CELL BIOLOGY INTERNATIONAL
Volume 40, Issue 12, Pages 1271-1279Publisher
WILEY
DOI: 10.1002/cbin.10655
Keywords
cardiac fibroblasts; DKK2; miR-154; myocardial infarction
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Excessive proliferation of cardiac fibroblasts (CFs) and their transdifferentiation into myofibroblasts leads to expression of a-smooth muscle actin (a-SMA), as well as excessive synthesis and secretion of collagens. This process represents an important pathological basis for myocardial fibrosis (MF). MicroRNA (miR)-154 and the Wnt signaling pathway play key roles in the above process, although their specific interactions are poorly understood. After transfecting CFs with miR-154 mimics or inhibitors, miR-154 was found to inhibit the expression of Dickkopf-related protein 2 (DKK2), while miR-154 inhibitors upregulated DKK2 expression in a Western blot analysis. In a subsequent dual-luciferase activity assay, direct binding of miR-154 to DKK2 was detected. Further experiments demonstrated that transfection of DKK2 siRNA or miR154 resulted in increased levels of b-catenin, a-SMA, and collagens I and III. Moreover, these changes were observed in association with increases in CF proliferation and migration, and reduced apoptosis. Conversely, transfection of miR-154 inhibitors or DKK2 overexpression vector resulted in lower expression levels of b-catenin, a-SMA, and collagens I and III, suppressed cell proliferation and migration, and enhanced apoptosis. Furthermore, in each assay, when the DKK2 overexpression vector and miR-154 mimics were co-transfected, the functions of each component were counteracted by the other. Therefore, in CFs, targeting of DKK2 by miR-154 leads to upregulation of b-catenin expression and activation of the classical Wnt signaling pathway and CFs. These results suggest new targets for the clinical treatment of MF and ischemic heart disease.
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