Canagliflozin improves early-stage cardiac hypertrophy and energy metabolism in TAC mice.

Early intervention in cardiac hypertrophy helps delay heart failure, but optimal intervention strategies remain unclear. We previously showed that cardiac energy metabolism changes dynamically during early cardiac hypertrophy. As a sodium-glucose cotransporter 2 inhibitor, canagliflozin (CANA) lowers blood glucose and modulates cardiac metabolic dysfunction. In this study, we examined the effects of CANA on early-stage cardiac hypertrophy in a transverse aortic constriction model using wild-type male C57BL/6J mice and investigated the underlying molecular mechanisms. CANA attenuated cardiac remodeling in TAC mice, reducing cardiomyocyte cross-sectional area, HW/BW ratio, and HW/TL ratio at day 7, and further decreasing left ventricular mass, wall thickness, and myocardial fibrosis at day 14. Furthermore, 18F-FDG micro-PET/CT imaging revealed stage-dependent regulation of myocardial glucose uptake by CANA, with increased uptake at day 7 and decreased uptake at day 14. Functional metabolic assays showed that CANA enhanced cardiac ATP production and fatty acid oxidation activity. Consistently, Western blot analysis indicated that CANA regulated key proteins involved in glucose and fatty acid oxidative metabolism, including mitochondrial pyruvate carrier 1 (MPC1) and carnitine palmitoyltransferase 1B (CPT1B). Importantly, pharmacological inhibition of MPC1 or CPT1B attenuated the protective effects of CANA and aggravated cardiac structural remodeling, suggesting that these two molecules are functionally involved in CANA-mediated cardioprotection. Thus, these findings suggest that CANA ameliorates early-stage cardiac hypertrophy, at least in part, by improving myocardial energy metabolism through coordinated regulation of glucose oxidation and fatty acid oxidation pathways, highlighting its potential as an early metabolic intervention strategy for cardiac hypertrophy.