Sotagliflozin improves cardiac remodeling and is associated with reduced ER stress–related apoptosis and fibrosis in a rat model of mitral regurgitation

Sotagliflozin (SOTA), a dual sodium–glucose cotransporter 1 and 2 (SGLT1/2) inhibitor, reduces adverse cardiovascular outcomes in patients with heart failure; however, its cardioprotective mechanisms in volume overload–induced heart failure remain incompletely understood. We hypothesized that SOTA attenuates maladaptive cardiac remodeling and dysfunction in mitral regurgitation (MR) by suppressing endoplasmic reticulum stress (ERS)–associated apoptosis and fibrotic remodeling. Chronic MR was induced in male Sprague–Dawley rats by mitral leaflet perforation. Four weeks after surgery, rats with MR were randomized to receive SOTA (30 mg/kg/day, oral gavage) or vehicle for six weeks. Cardiac geometry and function were assessed by echocardiography, while myocardial apoptosis, fibrosis, and molecular signaling pathways were evaluated using TUNEL assay, histological staining, Western blotting, and real-time RT-PCR. MR resulted in progressive chamber dilation, impaired systolic function, cardiomyocyte hypertrophy and apoptosis, and myocardial fibrosis. SOTA treatment attenuated left ventricular remodeling and reduced left atrial enlargement, restored ejection fraction, reduced cardiomyocyte apoptosis, and decreased myocardial fibrosis. SOTA treatment was associated with a lower myocardial SGLT1/SGLT2 protein ratio and reduced transcriptional activation of ERS-associated apoptotic pathways, including PERK–eIF2α–ATF4, IRE1–TRAF2, and CHOP-related signaling, accompanied by decreased profibrotic gene expression. These findings suggest that SOTA may mitigate cardiac dysfunction and adverse remodeling in MR-induced heart failure, potentially through attenuation of ERS-associated apoptotic and fibrotic signaling pathways. This study supports the therapeutic relevance of dual SGLT1/SGLT2 inhibition in chronic volume overload.