Short-Term Oral Administration of the Porcupine Inhibitor, Wnt-c59, Improves the Structural and Functional Features of Experimental HFpEF.

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases globally, and this incidence is increasing due to extended lifespans and accumulating comorbidities. Emerging evidence suggests that Wnt signaling plays a role in cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Furthermore, Porcupine (PORCN) inhibitors, which negatively regulate Wnt signaling, have shown promising results in improving cardiac function and reducing cardiac hypertrophy and/or fibrosis. This study investigated whether acute oral administration of the PORCN inhibitor, Wnt-c59, alters the maladaptive structural and/or functional features in a mouse model of HFpEF. Male mice were given a high-fat diet and L-NAME (0.5 g L^-1) in drinking water for 5 weeks, followed by a 2-week intervention of orally administered Wnt-c59 (5 mg kg^-1 day^-1). HFpEF mice were characterized by hypertension, cardiac hypertrophy and fibrosis, and diastolic dysfunction, although there was no evidence of activation of Wnt signaling in the heart. Despite this, short-term treatment of HFpEF mice with Wnt-c59 ameliorated adverse cardiac remodeling by increasing the ratio of the more compliant collagen type 3 to that of the more tensile collagen type 1 in the heart. Furthermore, Wnt-c59 also improved diastolic dysfunction, which was associated with the increased cardiac expression of brain natriuretic peptide, a known promoter of ventricular compliance. Our findings demonstrate that even short-term administration of a PORCN inhibitor improves both the structural and functional features of experimental HFpEF.