Information from the abstract
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.
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Related topics: Cardiac Fibrosis and Remodeling · Cardiovascular Function and Risk Factors · Endoplasmic Reticulum Stress and Disease
Thai researcher and institutional participation
Van Nhut Khanh Dong · Sushawadee Tongta · Pakit Boonpala · Nakkawee Saengklub · Yaowalak Panyasing · Sayamon Srisuwatanasagul · Promporn Raksaseri · Sirinapa Srikam · Wilawan Ji‐au · Sarawut Kumphune · Sarinee Kalandakanond‐Thongsong · Saikaew Sutayatram · Anusak Kijtawornrat · Chulalongkorn University · Mahidol University · King Chulalongkorn Memorial Hospital · Chiang Mai University
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