title: Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway.
abstract: To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3 interferes 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 of cardiomyopathy and heart failure.
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Bao
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Ge
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002460:Cell Line; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins