Bao Ming-Wei, Cai Zhongxiang, Zhang Xiao-Jing, Li Liangpeng, Liu Xiaoxiong, Wan Nian, Hu Gangying, Wan Fengwei, Zhang Rui, Zhu Xueyong, Xia Hao, Li Hongliang
Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
Basic Res Cardiol. 2015 May;110(3):25. doi: 10.1007/s00395-015-0481-x. Epub 2015 Apr 4.
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.
Dickkopf-3（DKK3）是Dickkopf家族（DKK1 - 4）的一种分泌型糖蛋白，可调节Wnt信号通路。据报道，DKK3可调节细胞发育、增殖、凋亡和免疫反应。然而，DKK3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DKK3在MI后重塑调节中的功能意义及其潜在机制。通过手术结扎左冠状动脉前降支，在表达心脏特异性DKK3的转基因小鼠、DKK3基因敲除（KO）小鼠及其非转基因和DKK3（+/+）同窝小鼠中诱导MI。我们的结果表明，MI后，缺乏DKK3的小鼠死亡率增加、梗死面积更大且左心室（LV）功能障碍加剧。值得注意的是，在MI后1周，与DKK3（+/+）同窝小鼠的心脏相比，DKK3 - KO小鼠的心脏凋亡增加、炎症加剧且LV重塑。相反，DKK3过表达在梗死后导致相反的表型。在体外暴露于缺氧的新生大鼠心肌细胞中也观察到了类似结果。机制上，DKK3通过中断ASK1 - JNK/p38信号级联促进心脏保护。总之，我们的结果表明，DKK3通过对ASK1 - JNK/p38信号通路的负调节来保护心脏免受MI诱导的心脏重塑。因此，我们的研究表明，DKK3可能是MI后心力衰竭治疗的潜在治疗靶点。
