Wnt-C59 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via Interruption of Wnt Pathway

BACKGROUND: Cardiac hypertrophy usually results in heart failure and is an important cause of mortality worldwide. Wnt/β-catenin signaling pathway hyper-activation is involved in the pathogenesis and progression of cardiac hypertrophy. Wnt-C59 is a small molecular compound, which strongly and specifically targets at Porcupine to pharmacologically inhibit Wnt palmitoylation, secretion, and other biological activities. However, the role of Wnt-C59 in cardiac hypertrophy remains unknown. MATERIAL/METHODS: We performed transverse aortic constriction (TAC) in adult male mice to induce pressure overload and establish an in vivo model of cardiac hypertrophy. Angiotensin II (Ang-II) was utilized to culture cardiomyocyte to establish a model of in vitro cardiomyocyte hypertrophy. Daily administration of Porcupine inhibitor Wnt-C59 was performed for 4 weeks after TAC surgery. RESULTS: Wnt-C59 significantly improved cardiac function and enhanced survival of mice subjected to TAC surgery. Histologically, Wnt-C59 attenuated TAC-induced increase in heart mass, cross-section area of cardiomyocyte, cardiac fibrosis, cardiomyocyte apoptosis, and expression of the hypertrophic biomarkers β-MHC, ANP, and BNP. TAC-induced oxidative stress was also ameliorated by Wnt-C59. Wnt-C59 attenuated Ang-II-induced in vitro cardiomyocyte hypertrophy, as indicated by decreased cell size and lower expression of ANP, BNP, and β-MHC. Moreover, Wnt/β-catenin activation was blocked by Wnt-C59 in cardiac hypertrophy, as indicated by decreased protein expression of Wnt3a and β-catenin and the Wnt target genes cyclin D1 and c-Myc. CONCLUSIONS: Collectively, Porcupine inhibitor Wnt-C59 attenuates pressure overload-induced cardiac hypertrophic via interruption of the Wnt/β-catenin signaling pathway, and it might be a promising drug for patients with cardiac hypertrophy.