β-Hydroxybutyrate Mitigated Heart Failure with Preserved Ejection Fraction by Increasing Treg Cells via Nox2/GSK-3β

Background This study was designed to investigate the cardioprotective role of β-hydroxybutyrate (BHB) in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanism. Methods A two-hit model with a high-fat diet (HFD) and Nω-nitrol-arginine methyl ester (L-NAME) was used as an HFpEF model. The treatment group received a weekly intraperitoneal injection of β-hydroxybutyrate (BHB). Cardiac function, inflammation, and fibrosis were evaluated. CD3+CD4+Foxp3+ positive cells within the myocardium were quantified by flow cytometry. The NADPH oxidase 2 (NOX2)/glycogen synthase kinase-3β (GSK3β) pathway was examined by immunoblot analysis. Results BHB improved diastolic function, fibrosis and cardiac remodeling in HFpEF. Additionally, BHB inhibited cardiac inflammation and increased cardiac Treg cells, which could be due to the downregulation of the NOX2/GSK-3β pathway. Conclusion BHB protected against the progression of HFpEF by increasing cardiac Treg cells by modulating the NOX2/GSK-3β pathway.