title: Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction.
abstract: Dickkopf-3 (DKK3) is a secreted glycoprotein of the Dickkopf family (DKK1-4) that modulates Wnt signalling. DKK3 has been reported to regulate cell development, proliferation, apoptosis, and immune response. However, the functional role of DKK3 in cardiac remodelling after myocardial infarction (MI) has not yet been elucidated. This study aimed to explore the functional significance of DKK3 in the regulation of post-MI remodelling and its underlying mechanisms. MI was induced by surgical left anterior descending coronary artery ligation in transgenic mice expressing cardiac-specific DKK3 and DKK3 knockout (KO) mice as well as their non-transgenic and DKK3(+/+) littermates. Our results demonstrated that after MI, mice with DKK3 deficiency had increased mortality, greater infarct size, and exacerbated left ventricular (LV) dysfunction. Significantly, at 1 week post-MI, the hearts of DKK3-KO mice exhibited increased apoptosis, inflammation, and LV remodelling compared with the hearts of their DKK3(+/+) littermates. Conversely, DKK3 overexpression led to the opposite phenotype after infarction. Similar results were observed in cultured neonatal rat cardiomyocytes exposed to hypoxia in vitro. Mechanistically, DKK3 promotes cardioprotection by interrupting the ASK1-JNK/p38 signalling cascades. In conclusion, our results indicate that DKK3 protects against the development of MI-induced cardiac remodelling via negative regulation of the ASK1-JNK/p38 signalling pathway. Thus, our study suggests that DKK3 may represent a potential therapeutic target for the treatment of heart failure after MI.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Bao
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Cai
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Li
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Liu
authors.forename: Nian
authors.initials: N
authors.lastname: Wan
authors.forename: Gangying
authors.initials: G
authors.lastname: Hu
authors.forename: Fengwei
authors.initials: F
authors.lastname: Wan
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.forename: Hao
authors.initials: H
authors.lastname: Xia
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D018925:Chemokines; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; C405061:Dkk3 protein, mouse; C498626:Dkk3 protein, rat; D036341:Intercellular Signaling Peptides and Proteins