A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy

Publication date: Available online 1 August 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Jiahui Jiang, Cong Lan, Liangpeng Li, Dezhong Yang, Xuewei Xia, Qiao Liao, Wenbin Fu, Xiongwen Chen, Songzhu An, Wei Eric Wang, Chunyu ZengAbstractWNT 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. Four-month-old male C57 mice were used in the experiments. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in-vivo. Angiotensin-II was used to induce cardiomyocyte hypertrophy in-vitro. 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 β-catenin and the elevation of Frizzled-2, cyclin-D1 and c-myc expression, indicating its inhibitory effect on canonical WNT pathway. ...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research