Cardioprotective effects of 3-N-Butylphthalide in diabetic cardiomyopathy: focus on balanced mitochondrial dynamics...

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, marked by myocardial dysfunction due to mitochondrial dysfunction and pyroptosis. 3-N-Butylphthalide (NBP), known for cardioprotective effects, remains unstudied in DCM. We evaluated NBP's therapeutic potential in a rat model of type 2 DCM, focusing on mitochondrial dynamics, mitophagy, and pyroptosis. Male Sprague-Dawley rats with DCM, induced by a high-fat diet and streptozotocin, were divided into five groups: control, DCM, DCM + NBP (100 mg/kg/day for 14 days' post-diabetes), DCM + Mdivi-1 (1.2 mg/kg/day), and DCM + NBP + Mdivi-1. Cardiac function was assessed by echocardiography; myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, mitochondrial dynamics, and function were analyzed via ELISA, hematoxylin and eosin staining, transmission electron microscopy, Western blot, and biochemical assays. DCM rats showed reduced ejection fraction and fractional shortening, increased left ventricular end-diastolic and systolic diameters, elevated cTnI and BNP, and histopathological damage. Inflammasome and pyroptosis markers (NLRP3, cleaved-caspase-1, ASC, GSDMD-N, IL-1β, LDH) increased, mitophagy (PINK1, Parkin) decreased, and mitochondrial function (ROS up, ATP down) worsened in DCM group. NBP improved cardiac function, reduced injury markers, and histopathology by suppressing inflammasome-pyroptosis, enhancing mitophagy, and restoring mitochondrial function and dynamics (Mfn2 up, Drp1 modulated). Co-treatment with Mdivi-1 attenuated these effects, indicating reliance on balanced mitochondrial dynamics. NBP mitigates DCM by enhancing mitochondrial homeostasis and inhibiting pyroptosis, but its efficacy diminishes with excessive fission inhibition. These findings suggest NBP's potential as a DCM therapy, meriting further clinical exploration.