Luo Cheng, Fang Chen, Zou Rongjun, Jiang Jingwei, Zhang Miao, Ge Teng, Zhou Hao, Fan Xiaoping, Zheng Baoshi, Zeng Zhiyu
Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China.
Theranostics. 2025 Mar 19;15(10):4507-4525. doi: 10.7150/thno.109514. eCollection 2025.
Hyperglycemia-induced endothelial dysfunction is a hallmark of diabetic cardiomyopathy, yet the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate how the DNA damage response (DDR) pathway regulates endothelial cell ferroptosis under hyperglycemic conditions, potentially revealing new therapeutic targets for mitigating cardiac damage in type 2 diabetes mellitus (T2DM). We performed an integrated analysis of publicly available RNA sequencing datasets (GSE280770, GSE89475, GSE161931, CRA007245) to evaluate the role of DDR in hyperglycemia-induced endothelial dysfunction and , including in a T2DM mouse model. Key DDR and ferroptosis markers were validated in cardiac microvascular endothelial cells (CMECs) isolated from mice with streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM, with and without treatment with the DNA-PK inhibitors NU7441 or M9831. Hyperglycemia induced a robust DDR in endothelial cells, characterized by the upregulation of DNA-PK complex genes (PRKDC, XRCC5, XRCC6) and increased markers of DNA damage (γH2AX, 8-oxo-dG). This was accompanied by increased expression of pro-ferroptotic genes (Tfrc, Acsl4, Ptgs2), decreased expression of anti-ferroptotic genes (Gpx4, Slc7a11), and elevated lipid peroxidation (MDA, 4-HNE). Pharmacological inhibition of DNA-PK mitigated these effects, reducing oxidative stress, lipid peroxidation, and endothelial permeability, while improving cardiac contractile and relaxation parameters. Our findings implicate the DNA-PK complex as a key regulator of hyperglycemia-induced endothelial ferroptosis in T2DM cardiomyopathy. Targeting DNA-PK complex may represent a novel therapeutic strategy for mitigating microvascular dysfunction and cardiac decline in T2DM.
高血糖诱导的内皮功能障碍是糖尿病心肌病的一个标志，但其潜在的分子机制仍未完全阐明。本研究旨在探讨DNA损伤反应（DDR）通路如何在高血糖条件下调节内皮细胞铁死亡，这可能为减轻2型糖尿病（T2DM）患者的心脏损伤揭示新的治疗靶点。我们对公开可用的RNA测序数据集（GSE280770、GSE89475、GSE161931、CRA007245）进行了综合分析，以评估DDR在高血糖诱导的内皮功能障碍中的作用，包括在T2DM小鼠模型中的作用。在从链脲佐菌素（STZ）/高脂饮食（HFD）诱导的T2DM小鼠中分离出的心脏微血管内皮细胞（CMECs）中，对DDR和铁死亡的关键标志物进行了验证，这些小鼠接受或未接受DNA-PK抑制剂NU7441或M9831治疗。高血糖在内皮细胞中诱导了强烈的DDR，其特征是DNA-PK复合基因（PRKDC、XRCC5、XRCC6）上调以及DNA损伤标志物（γH2AX、8-氧代-dG）增加。这伴随着促铁死亡基因（Tfrc、Acsl4、Ptgs2）表达增加、抗铁死亡基因（Gpx4、Slc7a11）表达降低以及脂质过氧化（MDA、4-HNE）升高。DNA-PK的药理学抑制减轻了这些作用，降低了氧化应激、脂质过氧化和内皮通透性，同时改善了心脏收缩和舒张参数。我们的研究结果表明，DNA-PK复合物是T2DM心肌病中高血糖诱导的内皮铁死亡的关键调节因子。靶向DNA-PK复合物可能代表一种减轻T2DM患者微血管功能障碍和心脏功能衰退的新治疗策略。
