Kong Chang, Ni Xuqing, Wang Yixiu, Zhang Anqi, Zhang Yingying, Lin Feihong, Li Shan, Lv Ya, Zhu Jingwen, Yao Xinyu, Dai Qinxue, Mo Yunchang, Wang Junlu
Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of General Practice, Wenzhou Central Hospital, 325000, Wenzhou, Zhejiang, China.
Cell Death Discov. 2022 Apr 9;8(1):187. doi: 10.1038/s41420-022-00957-y.
Previous studies have demonstrated that cardiomyocyte apoptosis, ferroptosis, and inflammation participate in the progress of sepsis-induced cardiomyopathy (SIC). Although Islet cell autoantigen 69 (ICA69) is an imperative molecule that could regulate inflammation and immune response in numerous illnesses, its function in cardiovascular disease, particularly in SIC, is still elusive. We confirmed that LPS significantly enhanced the expression of ICA69 in wild-type (WT) mice, macrophages, and cardiomyocytes. The knockout of ICA69 in lipopolysaccharide(LPS)-induced mice markedly elevated survival ratio and heart function, while inhibiting cardiac muscle and serum inflammatory cytokines, reactive oxygen (ROS), and ferroptosis biomarkers. Mechanistically, increased expression of ICA69 triggered the production of STING, which further resulted in the production of intracellular lipid peroxidation, eventually triggering ferroptosis and heart injury. Intriguingly, ICA69 deficiency only reversed the ferroptotic marker levels, such as prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), 4-hydroxynonenal (4HNE), glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), iron and lipid ROS, but had no effects on the xCT-dependent manner. Additionally, greater ICA69 level was identified in septic patients peripheralblood mononuclear cells (PBMCs) than in normal control groups. Generally, we unveil that ICA69 deficiency can relieve inflammation and ferroptosis in LPS-induced murine hearts and macrophages, making targeting ICA69 in heart a potentially promising treatment method for SIC.
先前的研究表明，心肌细胞凋亡、铁死亡和炎症参与了脓毒症诱导的心肌病（SIC）的进展。尽管胰岛细胞自身抗原69（ICA69）是一种在多种疾病中可调节炎症和免疫反应的重要分子，但其在心血管疾病，尤其是在SIC中的作用仍不清楚。我们证实，脂多糖（LPS）显著增强了野生型（WT）小鼠、巨噬细胞和心肌细胞中ICA69的表达。在脂多糖（LPS）诱导的小鼠中敲除ICA69可显著提高生存率和心脏功能，同时抑制心肌和血清炎症细胞因子、活性氧（ROS）和铁死亡生物标志物。机制上，ICA69表达增加触发了干扰素基因刺激蛋白（STING）的产生，这进一步导致细胞内脂质过氧化的产生，最终引发铁死亡和心脏损伤。有趣的是，ICA69缺乏仅逆转了铁死亡标志物水平，如前列腺素内过氧化物合酶2（PTGS2）、丙二醛（MDA）、4-羟基壬烯醛（4HNE）、谷胱甘肽过氧化物酶4（GPX4）、超氧化物歧化酶（SOD）、铁和脂质ROS，但对xCT依赖方式没有影响。此外还发现，脓毒症患者外周血单核细胞（PBMCs）中的ICA69水平高于正常对照组。总体而言，我们发现ICA69缺乏可减轻LPS诱导的小鼠心脏和巨噬细胞中的炎症和铁死亡，使靶向心脏中的ICA69成为一种对SIC具有潜在前景的治疗方法。
