Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats.

Abstract

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia. A key pathological feature of AF is atrial fibrosis, which promotes arrhythmogenic remodeling. While myocardial fibrosis has been widely observed in AF models, the underlying molecular mechanisms driving fibrotic progression remain incompletely understood. AF rats were modeled using acetylcholine, followed by treatment with different concentrations of dapagliflozin (DAPA) or positive control amiodarone. To elucidate the role of the high-mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) pathway in AF, lipopolysaccharide (LPS; an HMGB1/RAGE pathway activator) and FPS-ZM1 (a RAGE inhibitor) were employed. Cardiac function, myocardial fibrosis, and inflammation-related proteins were assessed using echocardiography, enzyme-linked immunosorbent assay, histological staining, Western blotting, and reverse transcription quantitative polymerase chain reaction. AF rats exhibited marked cardiac dysfunction, fibrosis, and increased expression of inflammatory markers. DAPA restored cardiac function, attenuating fibrosis and inflammation. LPS aggravated cardiac injury, while DAPA attenuated the damage, with the greatest protective effects observed in the LPS + DAPA + FPS-ZM1 group. DAPA attenuates atrial fibrosis and cardiac dysfunction in AF rats by inhibiting the HMGB1/RAGE pathway. This study suggests the potential of DAPA as a therapeutic option for AF.