Abstract Body: Background: Metabolic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) are major causes of cardiac-related hospitalization and mortality, and effective therapies remain limited despite improved understanding of disease mechanisms. Protein Tyrosine Phosphatase 1B (PTP1B), a negative regulator of insulin signaling, is an emerging target for obesity, insulin resistance, and diabetes, nodal predisposing factors for HFpEF. Our recent study shows that PTP1B inhibition in cardiomyocytes protects against high-fat diet (HFD)-induced cardiomyopathy. Here, we hypothesized that the inhibition of PTP1B may also protect against development and progression of HFpEF.
Methods: To assess the role of cardiac PTP1B, 8-week-old mice with cardiomyocyte-specific PTP1B deletion (PTP1B^fl/fl::αMHC^Cre/+) were fed either a normal diet (ND) or a "two-hit" HFpEF diet (HFD + L-NAME) for 15 weeks. In a parallel therapeutic study, wild-type C57BL/6J mice were placed on an HFpEF diet for 10 weeks to establish the phenotype, followed by an additional 10 weeks of diet plus or minus Trodusquemine (2.5 mg/kg, i.p.), a selective PTP1B inhibitor. Metabolic health was analyzed via body weight (BW), glucose and insulin tolerance tests, while cardiac function was evaluated using echocardiography.
Results: Cardiomyocyte-specific deletion of PTP1B prevented cardiac hypertrophy and HFpEF phenotype in mice exposed to the HFpEF diet. In wild-type mice with established HFpEF, Trodusquemine treatment significantly reduced BW and improved glucose tolerance and insulin sensitivity. Echocardiography revealed reduced hypertrophy and improved diastolic function. Upon sacrifice, heart weight was lower in PTP1B^fl/fl::αMHC^Cre/+ mice and treated groups, as compared to their respective controls. Histology indicated reduced cardiac lipid accumulation (Oil Red O staining), fibrosis (Masson’s trichrome staining) and reduced cell size (Hematoxylin and Eosin staining). Phosphoproteomic analysis further confirmed that PTP1B inhibition effectively rescued the cardiac signaling profile from the HFpEF state.
Conclusions: PTP1B inhibition attenuates metabolic dysfunction-induced cardiomyopathy and HFpEF, supporting PTP1B as a promising therapeutic target for HFpEF treatment.