L-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation
L-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation
复制标题
DOI：
10.1016/j.ejphar.2017.04.003
复制
发表时间：
2017-06-05
影响因子：
5
通讯作者：
Cai, Hui
中科院分区：
文献类型：
--
作者：
Fan, Zhigang;Han, Yang;Cai, Hui
放射性心脏损伤（RIHD）目前被认为是接受放射治疗的癌症患者死亡的原因之一。心功能损害是RIHD的临床表现。左旋卡尼汀对辐射和心脏病有保护作用。本研究旨在探讨L-卡尼汀对RIHD的心肌保护作用及其可能的分子机制。将小鼠心脏暴露于γ辐射以诱导RIHD。以100 mg/Kg和200 mg/Kg的剂量使用L-肉毒碱腹膜内处理动物。此外，通过腹膜内注射使用p38 MAPK的特异性抑制剂来治疗动物。采用侵入性血流动力学方法测定心脏收缩/舒张功能;采用TUNEL法评估心肌细胞凋亡;采用DHE染色测量细胞内活性氧产生;采用Western印迹法评估p38 MAPK磷酸化、Nrf 2磷酸化以及HO 1、NQO 1、caspase 3和bax表达水平。左旋卡尼汀治疗可抑制辐射引起的心功能损害。放射暴露诱导心肌细胞凋亡和活性氧的产生，这是衰减的L-肉毒碱治疗。然而，施用p38 MAPK抑制剂（SB 203580）显著损害了L-肉碱对减弱辐射心脏中细胞凋亡、活性氧积累和心脏功能的作用。我们的研究表明，L-肉毒碱管理激活p38 MAPK/Nrf 2信号，启动HO 1和NQO 1的表达，分别具有抗凋亡和抗氧化作用。总之，左旋卡尼汀通过抑制放射性心脏中活性氧的产生和细胞凋亡来减轻心脏功能丧失。左旋卡尼汀的心肌保护作用是通过p38 MAPK/Nrf 2信号通路介导的。
Radiation-induced heart damage (RIHD) is now considered to be one of the causes of mortality in cancer patients undergoing radiotherapy. Cardiac function impairments are clinical manifestations of RIHD. L-carnitine shows protective effects against irradiation and heart disease. This study was aimed to investigate the cardioprotective effects and potential molecular mechanisms of L-carnitine against RIHD. Mouse hearts were exposed to gamma-radiation to induce RIHD. L-carnitine at doses of 100 mg/Kg and 200 mg/Kg was used to treat animals intraperitoneally. Additionally, a specific inhibitor of p38 MAPK was used to treat animals by intraperitoneal injections. Cardiac systolic/diastolic functions were determined using invasive hemodynamic methods; myocyte apoptosis was assessed using the TUNEL assay; intracellular reactive oxygen species production was measured using DHE staining; and western blotting was used to evaluate the phosphorylation of p38MAPK, phosphorylation of Nrf2, and expression levels of HO1, NQO1, caspase3 and bax. L-carnitine treatments inhibited irradiation induced cardiac function impairments. Radiation exposure induced myocyte apoptosis and reactive oxygen species production, which were attenuated by L-carnitine treatments. However, administration of a p38 MAPK inhibitor (SB203580) dramatically impaired L-carnitine's effect on attenuating apoptosis, reactive oxygen species accumulation and cardiac functions in irradiated hearts. Our study showed that L-carnitine administration activated p38MAPK/Nrf2 signalling, initiating the expression of HO1 and NQO1, which have anti-apoptotic and anti-oxidative effects, respectively. In conclusion, L-carnitine attenuates cardiac function loss by inhibiting reactive oxygen species production and apoptosis in hearts exposed to radiation. The cardioprotective effects of L-carnitine were mediated by p38MAPK/Nrf2 signalling.