4-辛基衣康酸减轻脂多糖诱导的心肌损伤

4-Octyl Itaconate Attenuates Lipopolysaccharide-Induced Myocardial Injury

目的探讨4-辛基衣康酸(4-OI)对脂多糖(LPS)诱导的小鼠心肌损伤的影响。方法采用6~8周雄性C57BL/6J小鼠,经腹腔注射4-OI(25 mg/kg)或等量生理盐水连续预处理3 d后,腹腔注射LPS(10 mg/kg)或等量生理盐水,12 h后行心脏超声检查。取心脏,行苏木精-伊红(HE)染色观察心肌病理变化;Western blot检测心肌组织中肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)、p65、pp65、谷胱甘肽过氧化物酶4(GPx4)、前列腺素内过氧化物合成酶2(PTGS2)和核转录因子红系2相关因子2(Nrf2)的蛋白表达水平。结果心脏超声结果显示,LPS腹腔注射后,小鼠左心室明显扩张,收缩功能减低;与LPS组相比,4-OI组小鼠左心室收缩功能改善。HE染色示LPS腹腔注射后,小鼠心脏炎症细胞浸润明显,心肌细胞排列疏松,表现出类似于脓毒症诱导的心肌损伤的病理特点。4-OI组小鼠心脏的炎症细胞浸润程度和病理改变较LPS组低。Western blot示LPS腹腔注射后,小鼠心肌组织中Nrf2和GPx4的表达明显降低,IL-1β、TNF-α、PTGS2以及pp65/p65表达明显升高;与LPS组相比,4-OI组小鼠心肌组织中的Nrf2和GPx4蛋白水平更高,而IL-1β、TNF-α、pp65/p65和PTGS2表达水平降低。结论4-OI预处理可通过减轻炎症和氧化应激,减轻LPS诱导造成的心肌损伤,从而保护心脏功能。

Objective To investigate the effect of 4-octyl itaconate(4-OI)on lipopolysaccharides(LPS)-induced myocardial injury in mice.Methods Male C57BL/6J mice of 6~8 weeks were injected intraperitoneally with 4-OI(25 mg/kg)or an equivalent amount of normal saline for continuous pretreatment for 3 days.LPS(10 mg/kg)or an equivalent amount of normal saline was injected intraperitoneally,and echocardiography was performed 12 hours later.The hearts were taken for hematoxylin and eosin(HE)staining to observe myocardial pathological changes;the protein expression levels of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),p65,pp65,glutathione peroxidase 4(GPx4),prostaglandin endoperoxide synthase 2(PTGS2),nuclear factor erythroid 2-related factor 2(Nrf2)in myocardial tissue were detected by Western blot.Results Cardiac ultrasound results showed that the left ventricle of mice significantly expanded and the systolic function decreased after LPS intraperitoneal injection;and compared with LPS group,the left ventricular systolic function in 4-OI group was improved.HE staining showed that the inflammatory cells in the heart of mice were significantly infiltrated and the arrangement of myocardial cells was loose after intraperitoneal injection of LPS,showing pathological characteristics similar to sepsis-induced myocardial injury.The degree of inflammatory cell infiltration and pathological changes in the heart of 4-OI group was lower than that of LPS group.Western blot showed that the expression of Nrf2 and GPx4 in myocardial tissue of mice were decreased significantly after intraperitoneal injection of LPS,but the expression of IL-1β,TNF-α,PTGS2 and pp65/p65 expression were increased significantly;and compared with LPS group,Nrf2 and GPx4 protein levels in myocardial tissue of 4-OI group were higher,while the expression levels of IL-1β,TNF-α,pp65/p65 and PTGS2 were decreased.Conclusion 4-OI pretreatment can protect cardiac function by reducing inflammation and oxidative stress,reducing LPS-induced myocardial damage.