title: l-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation.
abstract: 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 γ-radiation to induce RIHD. L-carnitine at doses of 100mg/Kg and 200mg/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.
authors.affiliation: Department of Oncology, No. 3201 Hospital of Xi'an Jiaotong University, China; The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China.
authors.forename: Yuanpeng
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, China. Electronic address: caihui9@stu.xjtu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002331:Carnitine / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D002331:Carnitine
keywords: Apoptosis; Cardiac function; L-carnitine; Radiation-induced heart damage; Reactive oxygen species