Xiang Hong, Lyu Qi, Chen Shuhua, Ouyang Jie, Xiao Di, Liu Quanjun, Long HaiJiao, Zheng Xinru, Yang Xiaoping, Lu Hongwei
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
Center for Experimental Medicine, The Third Xiangya Hospital of Central South University, Changsha, China.
Cardiovasc Diabetol. 2024 Dec 4;23(1):432. doi: 10.1186/s12933-024-02514-6.
The pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression.
Cardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues.
The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.
糖尿病性心肌病（DCM）的病理生理学是一个备受关注的现象，但其临床问题尚未得到有效解决。近年来，包括DCM在内的各种疾病病理生理学中的铁死亡机制引起了广泛关注。在此，我们通过下调PACS2表达来探讨PACS2在DCM铁死亡中的作用。
用高糖和棕榈酸（HGPA）处理心肌细胞，对心肌细胞铁离子、脂质过氧化物和活性氧（ROS）的检测显示，在这些处理过程中存在明显的铁死亡。沉默PACS2可显著下调CPT1A表达并上调DHODH表达，逆转HGPA诱导的铁死亡。用CPT1A激动剂进一步沉默PACS2会加剧心肌细胞铁死亡，同时促进心肌细胞的线粒体损伤。使用链脲佐菌素（STZ）和高脂饮食（HFD）诱导的2型糖尿病小鼠模型，我们发现缺失PACS2可逆转这些处理诱导的心肌组织中细胞铁离子增加、心脏功能受损、线粒体损伤和铁死亡。
PACS2/CPT1A/DHODH信号通路可能通过调节心肌细胞线粒体功能参与DCM的铁死亡。
