A novel porcupine inhibitor blocks WNT pathways and attenuates cardiac hypertrophy

Abstract

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 β-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.