SGLT2i attenuates biventricular remodeling and preserves connexin 43 in experimental volume-overload heart failure
- 1Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research
- 2Center for Experimental Medicine, Institute for Clinical and Experimental Medicine
- 3Department of Cardiology, Faculty of Medicine, National Cardiovascular Institute, Comenius University
Abstract
Heart failure (HF) caused by chronic volume overload is associated with progressive structural, electrical, and metabolic remodeling, leading to ventricular dysfunction and increased arrhythmogenic risk. Although sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide significant cardioprotection, their glucose-independent mechanisms remain incompletely understood. This study examined the effects of the SGLT2i empagliflozin on biventricular myocardial remodeling in a rat model of volume-overload HF induced by aortocaval fistula (ACF), with emphasis on extracellular matrix (ECM) remodeling and gap-junctional communication. Volume overload resulted in pronounced cardiac hypertrophy, ventricular dilation, fibrosis, oxidative stress, and cellular injury, accompanied by reduced and mislocalized connexin 43 (Cx43) and increased connexin 45 (Cx45) expression. These changes were associated with elevated pro-fibrotic and stress markers (GDF15, Galectin-3, FGF21) and altered protein kinase C (PKC) signaling. SGLT2i treatment significantly attenuated hypertrophy, reduced collagen deposition, oxidative stress, and tissue damage, and partially improved systolic function. Importantly, SGLT2i preserved Cx43 expression and Ser368 phosphorylation, prevented maladaptive Cx45 upregulation, and improved ECM remodeling. Modulation of PKCε and PKCδ suggests activation of protective intracellular pathways. In conclusion, SGLT2i exerts multifaceted cardioprotective effects in volume-overload HF independent of glycemic control, improving structural and electrical myocardial integrity and potentially reducing arrhythmogenic risk.
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BibTeX
@article{sykora2026sglt2i,
title = {{SGLT2i attenuates biventricular remodeling and preserves connexin 43 in experimental volume-overload heart failure}},
author = {Matus Sykora and Katarina Ondrejak Andelova and Veronika Farkasova and Tamara Egan Benova and Natalia Andelova and Zuzana Honetschlagerova and Eva Goncalvesova and Narcis Tribulova and Barbora Szeiffova Bacova},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-64369-z},
url = {https://doi.org/10.1038/s41598-026-64369-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - SGLT2i attenuates biventricular remodeling and preserves connexin 43 in experimental volume-overload heart failure
AU - Matus Sykora
AU - Katarina Ondrejak Andelova
AU - Veronika Farkasova
AU - Tamara Egan Benova
AU - Natalia Andelova
AU - Zuzana Honetschlagerova
AU - Eva Goncalvesova
AU - Narcis Tribulova
AU - Barbora Szeiffova Bacova
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-64369-z
UR - https://doi.org/10.1038/s41598-026-64369-z
AB - Heart failure (HF) caused by chronic volume overload is associated with progressive structural, electrical, and metabolic remodeling, leading to ventricular dysfunction and increased arrhythmogenic risk. Although sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide significant cardioprotection, their glucose-independent mechanisms remain incompletely understood. This study examined the effects of the SGLT2i empagliflozin on biventricular myocardial remodeling in a rat model of volume-overload HF induced by aortocaval fistula (ACF), with emphasis on extracellular matrix (ECM) remodeling and gap-junctional communication. Volume overload resulted in pronounced cardiac hypertrophy, ventricular dilation, fibrosis, oxidative stress, and cellular injury, accompanied by reduced and mislocalized connexin 43 (Cx43) and increased connexin 45 (Cx45) expression. These changes were associated with elevated pro-fibrotic and stress markers (GDF15, Galectin-3, FGF21) and altered protein kinase C (PKC) signaling. SGLT2i treatment significantly attenuated hypertrophy, reduced collagen deposition, oxidative stress, and tissue damage, and partially improved systolic function. Importantly, SGLT2i preserved Cx43 expression and Ser368 phosphorylation, prevented maladaptive Cx45 upregulation, and improved ECM remodeling. Modulation of PKCε and PKCδ suggests activation of protective intracellular pathways. In conclusion, SGLT2i exerts multifaceted cardioprotective effects in volume-overload HF independent of glycemic control, improving structural and electrical myocardial integrity and potentially reducing arrhythmogenic risk.
SN - 2045-2322
ER -