The SGLT2 inhibitor canagliflozin attenuates mitochondrial oxidative stress and alterations of calcium handling induced by high glucose in human cardiac fibroblasts.

Cardiac fibrosis and remodeling are critical contributors to heart failure, particularly in the context of diabetes, where hyperglycemia (HG) exacerbates pathological fibroblast activity. Despite the known cardiovascular benefits of canagliflozin (CANA), its specific effects on human cardiac fibroblasts (HCFs) under HG conditions remain unexplored. We investigated whether CANA could mitigate HG-induced detrimental responses in HCFs. Dose-response assays revealed that 100 nM CANA significantly reduced HG-induced proliferation and migration of HCFs. Furthermore, CANA attenuated mitochondrial reactive oxygen species (ROS) production, a key driver of myofibroblast differentiation, and suppressed HG-induced expression of SMAD2, a critical activator of cardiac fibroblasts. Additionally, HG disrupted calcium (Ca(2+)) homeostasis, which was ameliorated by CANA treatment. These findings collectively demonstrate that CANA exerts protective effects on HCFs by improving mitochondrial function, restoring Ca(2+) handling, and reducing fibroblast proliferation, migration, and activation under HG conditions.