Ma Dan, Fang Weilun, Cai Lei, Li Wei, Su Han
Department of General Surgery, The Third Xiangya Hospital, Central South University, 138# Tongzipo Road, Changsha, 410013, Hunan, China.
Department of Obstetrics and Gynecology, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.
Crit Care. 2025 Aug 13;29(1):354. doi: 10.1186/s13054-025-05602-5.
Norepinephrine (NE) is a first-line vasopressor for patients with septic shock, and its overuse can lead to "catecholamine adverse effects", including cardiovascular diseases. Lipopolysaccharide (LPS)-induced cardiomyopathy is one of the leading causes of mortality in septic patients. Previous studies have revealed that catecholamine can accentuate LPS-induced cardiomyopathy, but the underlying mechanisms remain elusive.
Adult mice and H9c2 cells were exposed to LPS and NE. Structural changes, cardiac function and LDH assays were measured to verify the synergistic effects of LPS and NE in vivo and in vitro. Inhibitors of ferroptosis, heme oxygenase-1 (HO-1) and an activator of SIRT3 were used to reverse the synergistic effects. 4-hydroxynonenal (4-HNE)/MDA assays, immunofluorescence, transmission electron microscopy (TEM) and western blotting were used to measure ferroptosis in this study.
In our study, conventional dosage of NE exacerbated LPS-induced cardiomyopathy in long term, followed by ferroptotic alternations of ferrous iron, reactive oxygen species (ROS), mitochondria shrinkage, lipid peroxidation and HO-1 expression. In addition, inhibition of ferroptosis suppressed cardiomyocyte death and cardiomyopathy induced by LPS and NE, indicating the critical contribution of ferroptosis to cardiac injury via the synergistic effects of NE and LPS. Our recent study identified SIRT3 as a therapeutic target for cardiac ferroptosis. In line with this, overexpression of SIRT3 alleviated the death of cardiomyocytes treated with NE + LPS, accompanied by attenuated ferroptosis and HO-1 level. Moreover, the suppression of HO-1 by zinc protoporphyrin (ZnPP) also attenuated ferroptosis in cardiomyocytes treated with NE and LPS.
These data strongly indicate that long-term use of NE can further develop LPS-induced cardiomyopathy via SIRT3/HO-1 axis-mediated ferroptosis.
去甲肾上腺素（NE）是感染性休克患者的一线血管升压药，其过度使用会导致“儿茶酚胺不良反应”，包括心血管疾病。脂多糖（LPS）诱导的心肌病是脓毒症患者死亡的主要原因之一。先前的研究表明，儿茶酚胺可加重LPS诱导的心肌病，但其潜在机制仍不清楚。
将成年小鼠和H9c2细胞暴露于LPS和NE。测量结构变化、心脏功能和LDH测定，以验证LPS和NE在体内和体外的协同作用。使用铁死亡抑制剂、血红素加氧酶-1（HO-1）和SIRT3激活剂来逆转协同作用。本研究采用4-羟基壬烯醛（4-HNE）/丙二醛（MDA）测定、免疫荧光、透射电子显微镜（TEM）和蛋白质印迹法检测铁死亡。
在我们的研究中，常规剂量的NE长期加重LPS诱导的心肌病，随后出现亚铁离子、活性氧（ROS）、线粒体收缩、脂质过氧化和HO-1表达的铁死亡改变。此外，抑制铁死亡可抑制LPS和NE诱导的心肌细胞死亡和心肌病，表明铁死亡通过NE和LPS的协同作用对心脏损伤起关键作用。我们最近的研究确定SIRT3是心脏铁死亡的治疗靶点。与此一致，SIRT3的过表达减轻了用NE+LPS处理的心肌细胞的死亡，同时铁死亡和HO-1水平降低。此外，锌原卟啉（ZnPP）对HO-1的抑制也减轻了用NE和LPS处理的心肌细胞中的铁死亡。
这些数据强烈表明，长期使用NE可通过SIRT3/HO-1轴介导的铁死亡进一步发展LPS诱导的心肌病。
