A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy
A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy
复制标题
一种新型豪猪抑制剂可阻断 WNT 通路并减轻心脏肥大
DOI：
10.1016/j.bbadis.2018.07.035
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发表时间：
2018-10-01
影响因子：
6.2
通讯作者：
Zeng, Chunyu
中科院分区：
文献类型：
--
作者：
Jiang, Jiahui;Lan, Cong;Zeng, Chunyu
WNT 通路与心脏肥大的生长密切相关。豪猪是一种能够特异性分泌所有 WNT 配体的酰基转移酶，成为抑制 WNT 通路的高度可药物化的靶标。我们在这里测试一种新型小分子豪猪抑制剂CGX1321是否具有抗肥厚作用，该抑制剂已作为抗癌剂进入人体临床试验。对四个月大的雄性 C57 小鼠进行横主动脉缩窄 (TAC) 来诱导心脏肥大。通过超声心动图测量心脏功能。进行组织学分析以检测心肌细胞大小和分子表达。 TAC 损伤后 4 周内每天给予 CGX1321。结果，CGX1321 改善了 TAC 后小鼠的心脏功能和动物存活率。 CGX1321显着减少TAC损伤引起的心肌细胞肥大、心肌细胞凋亡和纤维化。 CGX1321 显着抑制 TAC 诱导的 β-catenin 核转位以及 Frizzled-2、cyclin-D1 和 c-myc 表达的升高，表明其对经典 WNT 通路的抑制作用。此外，CGX1321 抑制 TAC 诱导的活化 T 细胞核因子的核转位和磷酸化 c-Jun 表达的升高，表明其对非经典 WNT 通路的抑制功能。我们得出的结论是，CGX1321 抑制经典和非经典 WNT 通路，并减轻心脏肥大。我们的研究结果支持豪猪抑制剂作为一类新药，有可能用于治疗心脏肥大患者。
WNT pathways are critically involved in the cardiac hypertrophy growth. Porcupine, an acyltransferase that specifically enables secretion of all WNT ligands, became a highly druggable target for inhibiting WNT pathways. Here we test if a novel small-molecule porcupine inhibitor CGX1321, which has entered human clinical trials as an anti-cancer agent, exerts an anti-hypertrophic effect. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy on four-month-old male C57 mice. Cardiac function was measured with echocardiography. Histological analysis was performed to detect cardiomyocyte size and molecular expressions. CGX1321 was administrated daily for 4 weeks post TAC injury. As a result, CGX1321 improved cardiac function and animal survival of post-TAC mice. CGX1321 significantly reduced cardiomyocyte hypertrophy, cardiomyocyte apoptosis and fibrosis induced by TAC injury. CGX1321 significantly inhibited TAC induced nuclear translocation of beta-catenin and the elevation of Frizzled-2, cyclin-D1 and c-myc expression, indicating its inhibitory effect on canonical WNT pathway. Furthermore, CGX1321 inhibited TAC induced nuclear translocation of nuclear factor of activated T-cells and the elevation of phosphorylated c-Jun expression, suggesting its inhibitory function on non-canonical WNT pathway. We conclude that CGX1321 inhibits both canonical and non canonical WNT pathways, and attenuates cardiac hypertrophy. Our findings support the porcupine inhibitors as a class of new drugs to be potentially used for treating patients with cardiac hypertrophy.