Gao Yifeng, Li En, Li Fang, Cui Ying, Shu Qi, Zhang Yan, Kong Lijuan, Li Han, Yang Xiaoyu
The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, People's Republic of China.
Pathology Teaching and Research Office, Zhengzhou Health Vocational College, Zhengzhou, 450001, People's Republic of China.
Cell Mol Life Sci. 2025 Jun 25;82(1):256. doi: 10.1007/s00018-025-05793-8.
Type 2 diabetes patients are particularly vulnerable to myocardial injury, including mitochondrial damage in the myocardium. This study aims to evaluate the therapeutic potential and mechanisms of dapagliflozin in mitigating myocardial mitochondrial injury under diabetic conditions.
A cell model was established using a high-glucose, high-fat combination. Dapagliflozin was dissolved in Dimethyl sulfoxide (DMSO) and added to the culture medium. A type 2 diabetic mouse model was induced by high-fat feeding combined with Streptozotocin (STZ) injection, with dapagliflozin administered via oral gavage. SORT1 was silenced using siRNA. Phenotypic evaluation and mechanistic analysis were performed through qPCR, Western blot (WB), activity assays, Reactive Oxygen Species (ROS) measurement, transmission electron microscopy, and Masson's staining.
In vitro studies, we demonstrated that under diabetic conditions, mitochondrial damage was evident, characterized by a decrease in mitochondrial respiratory chain complex content, reduced complex activity, increased ROS levels, and structural damage to mitochondria. Silencing SORT1 resulted in a similar mitochondrial phenotype under diabetic conditions, highlighting the critical role of sortilin in mitochondrial function. Addition of dapagliflozin to the culture medium significantly improved mitochondrial dysfunction caused by high glucose and high fat, a finding also confirmed in the mouse model. Moreover, dapagliflozin alleviated myocardial fibrosis induced by diabetes in the mouse model.
Our findings uncover a novel molecular mechanism through which dapagliflozin improves myocardial mitochondrial injury under diabetic conditions, suggesting SORT1 as a potential therapeutic target for treating myocardial injury in diabetes.
2型糖尿病患者特别容易发生心肌损伤，包括心肌线粒体损伤。本研究旨在评估达格列净在减轻糖尿病状态下心肌线粒体损伤方面的治疗潜力及机制。
采用高糖、高脂联合建立细胞模型。将达格列净溶解于二甲基亚砜（DMSO）中并添加到培养基中。通过高脂喂养联合链脲佐菌素（STZ）注射诱导建立2型糖尿病小鼠模型，经口灌胃给予达格列净。使用小干扰RNA（siRNA）沉默SORT1。通过定量聚合酶链反应（qPCR）、蛋白质免疫印迹法（WB）、活性测定、活性氧（ROS）测量、透射电子显微镜检查和Masson染色进行表型评估和机制分析。
在体外研究中，我们证明在糖尿病条件下，线粒体损伤明显，其特征为线粒体呼吸链复合物含量降低、复合物活性降低、ROS水平升高以及线粒体结构损伤。在糖尿病条件下沉默SORT1导致类似的线粒体表型，突出了sortilin在线粒体功能中的关键作用。向培养基中添加达格列净可显著改善高糖和高脂引起的线粒体功能障碍，这一发现也在小鼠模型中得到证实。此外，达格列净减轻了小鼠模型中糖尿病诱导的心肌纤维化。
我们的研究结果揭示了达格列净在糖尿病条件下改善心肌线粒体损伤的一种新分子机制，表明SORT1作为治疗糖尿病心肌损伤的潜在治疗靶点。
