Impact of Dapagliflozin on the Physiology of Rat and Human Cardiac Fibroblasts Under Diabetic Culture Conditions

Background and Objective: Heart failure (HF), characterized by impaired ventricular filling and ejection due to myocardial dysfunction, frequently arises from left ventricular impairment and is associated with conditions affecting the myocardium, pericardium, heart valves, and great vessels. This study aimed to evaluate the effects of dapagliflozin (dapa) on cardiac fibroblast (CF) physiology under diabetic conditions using rat (RcFbs) and human cardiac fibroblasts (HcFbs). Materials and Methods: Cardiac fibroblasts were cultured in diabetic media with or without dapagliflozin. Quantitative PCR was used to assess gene expression of collagen-1 (col1a2), calcium/calmodulin-dependent protein kinase II delta (CAMK2D), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Calcium mobilization was analyzed by confocal microscopy, while proliferation and migration were evaluated using a Countess counter and scratch wound assay. Data were statistically analyzed using appropriate parametric or non-parametric tests. Results: Dapagliflozin enhanced Ca²⁺ mobilization and promoted wound closure, indicating improved fibroblast migration. It significantly increased cell proliferation under diabetic conditions. Gene expression analysis revealed a decrease in col1a2 expression, while CAMK2D expression remained unchanged with dapagliflozin treatment. Conclusion: Dapagliflozin improves key physiological functions of cardiac fibroblasts under diabetic conditions, including Ca²⁺ mobilization, proliferation, and wound healing. Although it reduced col1a2 expression, its neutral effect on CAMK2D suggests selective gene modulation. These findings highlight the potential of dapagliflozin as a therapeutic candidate for HF, particularly HFpEF, and support further investigation into its mechanisms of action and clinical applications.