Cardioprotective Effects of Dapagliflozin and Trimetazidine on Doxorubicin-Induced Cardiotoxicity in Streptozotocin-Induced Type 1 Diabetic Rats via Endoplasmic Reticulum Stress

<b>Background/Objectives:</b> Diabetic cardiomyopathy is a distinct myocardial dysfunction characterized by structural and functional changes in the heart that occur in diabetic patients independently of coronary artery disease or hypertension. It is closely associated with oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, and contributes to progressive cardiac damage. This study aimed to evaluate the cardioprotective effects of dapagliflozin (DAPA) and trimetazidine (TMZ) in a rat model of doxorubicin-induced cardiomyopathy with streptozotocin-induced diabetes, focusing on their potential mechanisms related to ER stress. <b>Methods:</b> A total of 48 Sprague Dawley rats aged 6-8 weeks were randomly distributed equally into six cages. The diabetes model was induced by intraperitoneal administration of streptozotocin (STZ) and rats with blood glucose levels above 250 mg/dL were considered diabetic. For those rats with diabetes, cardiotoxicity was induced by intraperitoneal injection of 5 mg/kg/week doxorubicin (DOXO) for 4 weeks. After a cumulative dose of 20 mg/kg doxorubicin, a week break was given, followed by the administration of TMZ (10 mg/kg) and/or DAPA (10 mg/kg) to the treatment groups. <b>Results:</b> STZ administration caused diabetes and significant degeneration in cardiomyocytes. With the addition of DOXO (STZ + DOXO), cardiomyocyte degeneration became more severe. When the study groups were histopathologically evaluated based on parameters of degenerative cardiomyocytes, vascular congestion, and edema, it was shown that both TMZ and DAPA, whether applied alone or in combination, reduced damage in heart tissue. Both TMZ and DAPA reduced cardiomyocyte damage, and their combination provided the lowest level of damage through the reduced ER stress pathway by reducing GRP 78 and CHOP positivity. <b>Conclusions:</b> TMZ and DAPA reduce ER stress and have protective effects against diabetic-induced cardiotoxicity. Combination therapy or TMZ was found to be more effective than DAPA in alleviating ER stress. Combination therapy appears to carry potential effects for reducing cardiac cell damage in individuals with diabetes.