Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction
Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction
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Dickkopf-3 可预防心肌梗塞后的心功能障碍和心室重塑。
DOI：
10.1007/s00395-015-0481-x
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发表时间：
2015-05-01
影响因子：
9.5
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
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作者：
Bao, Ming-Wei;Cai, Zhongxiang;Li, Hongliang
Dickkopf-3（DKK 3）是调节Wnt信号传导的Dickkopf家族（DKK 1 -4）的分泌型糖蛋白。据报道，DKK 3调节细胞发育、增殖、凋亡和免疫应答。然而，DKK 3在心肌梗死（MI）后心脏重塑中的功能作用尚未阐明。本研究旨在探讨DKK 3在心肌梗死后重构调控中的作用及其机制。在表达心脏特异性DKK 3的转基因小鼠和DKK 3敲除（KO）小鼠以及它们的非转基因和DKK 3（+/+）同窝仔中，通过外科左前降支冠状动脉结扎诱导MI。我们的研究结果表明，MI后，DKK 3缺乏的小鼠死亡率增加，梗死面积更大，左心室（LV）功能障碍加重。值得注意的是，在MI后1周，与其DKK 3（+/+）同窝小鼠的心脏相比，DKK 3-KO小鼠的心脏表现出增加的细胞凋亡、炎症和LV重构。相反，DKK 3过表达导致梗死后相反的表型。在体外培养的缺氧新生大鼠心肌细胞中观察到类似的结果。从机制上讲，DKK 3通过中断ASK 1-JNK/p38信号级联来促进心脏保护。总之，我们的研究结果表明，DKK 3通过ASK 1-JNK/p38信号通路的负调节来防止MI诱导的心脏重构的发展。因此，我们的研究表明，DKK 3可能是一个潜在的治疗心肌梗死后心力衰竭的治疗靶点。
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.