Ogutveren Muhammed Mursel, Satiroglu Omer, Ozden Zulkar, Akyildiz Kerimali, Yilmaz Adnan, Mercantepe Filiz, Yilmaz Ahmet Seyda, Koc Haldun, Mercantepe Tolga
Department of Cardiology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey.
Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey.
J Clin Med. 2025 Feb 16;14(4):1315. doi: 10.3390/jcm14041315.
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. 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. 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. 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.
糖尿病性心肌病是一种独特的心肌功能障碍，其特征是糖尿病患者心脏发生结构和功能变化，且独立于冠状动脉疾病或高血压。它与氧化应激、炎症、线粒体功能障碍和内质网（ER）应激密切相关，并导致进行性心脏损伤。本研究旨在评估达格列净（DAPA）和曲美他嗪（TMZ）在链脲佐菌素诱导糖尿病的阿霉素诱导性心肌病大鼠模型中的心脏保护作用，重点关注其与内质网应激相关的潜在机制。总共48只6 - 8周龄的Sprague Dawley大鼠被随机均分到六个笼子中。通过腹腔注射链脲佐菌素（STZ）诱导糖尿病模型，血糖水平高于250 mg/dL的大鼠被视为糖尿病大鼠。对于那些糖尿病大鼠，通过腹腔注射5 mg/kg/周阿霉素（DOXO），持续4周来诱导心脏毒性。在累积剂量达20 mg/kg阿霉素后，给予一周休息期，随后治疗组给予TMZ（10 mg/kg）和/或DAPA（10 mg/kg）。STZ给药导致糖尿病和心肌细胞显著变性。加入DOXO（STZ + DOXO）后，心肌细胞变性变得更严重。当根据变性心肌细胞、血管充血和水肿参数对研究组进行组织病理学评估时，结果显示TMZ和DAPA单独或联合应用均能减少心脏组织损伤。TMZ和DAPA均能减少心肌细胞损伤，且它们的联合应用通过降低GRP 78和CHOP阳性率，通过减少内质网应激途径提供了最低水平的损伤。TMZ和DAPA可减轻内质网应激，并对糖尿病诱导的心脏毒性具有保护作用。发现联合治疗或TMZ在减轻内质网应激方面比DAPA更有效。联合治疗似乎对减少糖尿病个体的心脏细胞损伤具有潜在作用。
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