Dapagliflozin attenuates post-infarction fibrosis via cardiomyocyte protection and fibroblast inhibition

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), has revolutionized the treatment of heart failure (HF). However, its potential therapeutic application and underlying mechanisms acute myocardial infarction (MI) remain inadequately explored. This study employed rat acute MI models and in vitro myocardial injury models using isoproterenol (ISO)-stimulated cardiomyocytes and cardiac fibroblasts. Our in vivo results demonstrated that DAPA significantly improved survival rates and enhanced cardiac function, as assessed by echocardiography. Mechanistically, we delineated a dual-pathway strategy through which DAPA attenuates adverse cardiac remodeling. In cardiac fibroblasts, DAPA directly suppressed profibrotic activation, evidenced by reduced secretion of Collagen I and III and downregulation of α-smooth muscle actin (α-SMA) expression. This effect was mediated through the inhibition of the pro-fibrotic Wnt/β-catenin signaling pathway. The critical role was confirmed by its pharmacological activation with CHIR99021, which completely abrogated the anti-fibrotic benefits of DAPA. Concurrently, in cardiomyocytes, DAPA protected cardiomyocytes by reducing oxidative stress, as evidenced by decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, alongside restored superoxide dismutase (SOD) activity, thereby suppressing cardiomyocyte apoptosis. Concurrently, DAPA mitigated inflammation by inhibiting CD68⁺ macrophage infiltration in injured myocardial tissue, reducing the expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and elevating the anti-inflammatory cytokine IL-10. Our integrated findings establish that DAPA mitigates post-MI cardiac fibrosis by concurrently inhibiting Wnt/β-catenin-driven fibroblast activation and alleviating oxidative stress-induced cardiomyocyte injury. This work not only elucidates a multifaceted mechanism but also solidifies DAPA's repurposing potential as a promising therapeutic agent to prevent adverse remodeling after acute MI.