Abstract
Canagliflozin (Cana), a sodium-glucose cotransporter 2 (SGLT2) inhibitor with additional affinity for SGLT1, has demonstrated cardioprotective effects. However, its role in modulating ventricular electrophysiology and structural remodeling under stress conditions remains insufficiently characterized. We have previously reported electrical and structural remodeling in a rat model of isoproterenol (ISP)-induced myocardial injury. In this study, we investigated the protective effects of Cana and its underlying mechanism in an ISP-induced myocardial injury model using Sprague Dawley rat hearts and in neonatal rat ventricular cardiomyocytes (NRVCMs). Our data revealed that Cana significantly suppressed ISP-induced prolongation of electrophysiological parameters, reduced oxidative stress, preserved mitochondrial function, and elevated ketone body levels. In NRVCMs, Cana -rather than β-hydroxybutyrate (βOHB)- improved mitochondrial integrity, attenuated apoptosis, and downregulated SGLT1, sodium-calcium exchanger 1 (NCX1), and sodium-hydrogen exchanger 1 (NHE1) expression. These effects were at least partly abolished by phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) inhibition. Collectively, these findings suggest that Cana modulates electrical remodeling and exerts cardioprotective effects by enhancing mitochondrial function and regulating calcium transport. These results underscore the therapeutic potential of Cana in cardiovascular diseases.