Background: The aim of the study was to investigate the protective effect of
canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-
salt diet was used to induce
heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining,
wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac
ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and
proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and
protein expression analysis. Results: In this study, CANA showed
diuretic, hypotensive,
weight loss, and increased intake of food and water. Dahl
salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed
left ventricular remodeling and diastolic dysfunction caused by
hypertension. After CANA treatment,
cardiac hypertrophy and
fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial
glucose metabolism and increased
fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-
adenosine 5'-monophosphate-activated
protein kinase (p-AMPK) and
sirtuin 1 (
SIRT1) and significantly induced the expression of
peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial
hypertrophy,
fibrosis, and
left ventricular diastolic dysfunction induced by
hypertension in DSS rats, possibly through the activation of the AMPK/
SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.