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Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway.

2017年12月21日 来源:

Lu DBao DDong WLiu NZhang XGao SGe WGao XZhang L.

Abstract

       To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3interferes with Wnt signaling in heart tissues remains unknown. Here, we demonstrate that strong Dkk3 expression was markedly downregulated in adult hearts from WT mice, and Dkk3 expression was upregulated suddenly in hearts from DCM mouse models. Using Dkk3 transgenic and knockout mice, as well as cTnT(R141W) transgenic mice, which manifests progressive chamber dilation and contractile dysfunction and has pathologic phenotypes similar to human DCM patients, we determined that transgenic expression of Dkk3 increased survival rate, improved cardiac morphology breakage and dysfunction, and ameliorated cardiac pathological changes in the cTnT(R141W) mice. In contrast, Dkk3 knockout reduced the survival rate and aggravated the pathological phenotypes of the cTnT(R141W) mice. The protective effects of Dkk3 appeared clearly at 3 months of age, peaked at 6 months of age, and decreased at 10 months of age in the cTnT(R141W) mice. Furthermore, we determined that Dkk3 upregulated Dvl1 (Dishevelled 1) and key proteins of the canonical Wnt pathway (cytoplasmic and nuclear β-catenin, c-Myc, and Axin2) and downregulated key proteins of the noncanonical Wnt pathway (c-Jun N-terminal kinase (JNK), Ca(2+)/calmodulin-dependent protein kinase II (CAMKII), and histone deacetylase 4 (HDAC4)). In contrast, Dkk3 knockout reversed these changes in the cTnT(R141W) mice. In summary, Dkk3 could prevent FDCM development in mice, especially in the compensatory stage, and probably through activation of the canonical and inhibition of the noncanonical Wnt pathway, which suggested that Dkk3 could serve as a therapeutic target for the treatment ofcardiomyopathy and heart failure.

全文下载:https://www.nature.com/articles/labinvest2015145