Mol Biomed. 2026 Oct 28;7(1):231. doi: 10.1186/s43556-026-00642-x.
ABSTRACT
Aortic stenosis (AS) is increasingly prevalent in ageing populations, yet no pharmacological therapy has been shown to modify its progression to heart failure (HF). Sodium glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in HF, but their effects in pressure overload-induced cardiac remodeling remain unclear. Here, we show that rats with long-term AS develop HF features, left ventricular dilation, and systolic and diastolic dysfunction, accompanied by increased oxidative stress, impaired antioxidant defenses, myocardial fibrosis, and transcriptional remodeling. Empagliflozin (10 mg/kg/day for 8 weeks) attenuated cardiac dysfunction and reduced HF features. At molecular level, empagliflozin prevented increase in lipid peroxidation, and decreased interstitial collagen deposition, while increasing glutathione peroxidase and matrix metalloproteinase-2 activity. Transcriptomic analysis identified 1,078 differentially expressed genes and revealed enrichment of pathways associated with extracellular matrix organization and signal transduction in AS. Empagliflozin predominantly regulated genes involved in cardiac contraction, mitochondrial membrane organization, apoptosis, and cell survival. Profibrotic and remodeling-associated genes were upregulated in AS, while empagliflozin induced a distinct transcriptional program associated with improved myocardial homeostasis. AS was associated with reduced activity of energy metabolism enzymes, which was not restored by empagliflozin. Collectively, these findings identify oxidative stress, extracellular matrix remodeling, and transcriptional reprogramming as mechanisms underlying cardiac dysfunction in AS. Empagliflozin mitigates cardiac remodeling and HF progression and modulates fibrosis and gene networks regulating cardiac function. These data highlight SGLT2 inhibition as a potential therapeutic strategy in pressure overload-induced heart failure.
PMID:42955596 | DOI:10.1186/s43556-026-00642-x