Abstract Body (Do not enter title and authors here): Background: Metabolic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) are major contributors to cardiac-related hospitalization and mortality. Despite advances in understanding the pathology, therapeutic options remain limited. 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. Increased PTP1B expression and activity are observed in heart, brain, muscle, and adipose tissues from obese or diabetic animals and humans. Our recent study shows that PTP1B inhibition in cardiomyocytes protects against high-fat diet (HFD)-induced cardiomyopathy through direct regulation of cardiac metabolic signaling. Here, we suggest that the inhibition of PTP1B may also protect against development and progression of HFpEF.
Methods: Six-week-old C57BL/6J mice were subjected to baseline measurements of body weight (BW), glucose (GTT) and insulin (ITT) tolerance, and echocardiography to evaluate cardiac structure (e.g., left ventricular thickness) and function (e.g., ejection fraction). Mice were then randomized into three dietary groups: normal (ND), HFD, and HFpEF diet (HFD plus 0.5 g/L L-NAME), designed to induce cardiac stress and metabolic dysfunction, for 10 weeks (to 16 weeks of age). BW, GTT, ITT and echocardiography measurements were taken again to establish obesity and HFpEF phenotypes. Mice were then subjected to an additional 10 weeks on ND, HFD, or HFpEF diets, plus or minus Trodusquemine, a selective PTP1B inhibitor (2.5 mg/kg, i.p.) (to 26 weeks of age), to establish the role of PTP1B in HFpEF.
Results: Our data show that Trodusquemine significantly reduced body weight in HFD and HFpEF mice. GTT and ITT results showed improved glucose tolerance and insulin sensitivity in treated mice. Echocardiography revealed reduced hypertrophy and improved diastolic function. Upon sacrifice, heart weight was lower in treated groups, as compared to controls. Molecular analyses showed upregulated expression of genes involved in fatty acid oxidation in cardiac tissues of treated mice. Histology indicated reduced cardiac lipid accumulation (Oil Red O staining) and fibrosis (Masson’s trichrome staining).
Conclusions: Our findings indicate PTP1B inhibition mitigates metabolic dysfunction and associated cardiac remodeling, suggesting that Trodusquemine may be a promising therapeutic candidate for treatment of HFpEF.