A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy

作者:Jiang, Jiahui; Lan, Cong; Li, Liangpeng; Yang, Dezhong; Xia, Xuewei; Liao, Qiao; Fu, Wenbin; Chen, Xiongwen; An, Songzhu; Wang, Wei Eric*; Zeng, Chunyu
来源:Biochimica et Biophysica Acta-Molecular Basis of Disease, 2018, 1864(10): 3459-3467.
DOI:10.1016/j.bbadis.2018.07.035

摘要

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.