title: Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury.
abstract: Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Shan-Juan
authors.initials: SJ
authors.lastname: Fang
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Peng-Yang
authors.initials: PY
authors.lastname: Li
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Lu
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Zhang
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Ma
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Chao-Shu
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China. Electronic address: spnie@126.com.
authors.forename: Shao-Ping
authors.initials: SP
authors.lastname: Nie
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address: yongfenqi@163.com.
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002316:Cardiotonic Agents / Q000008:administration & dosage; D053454:Caspase 12 / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002316:Cardiotonic Agents; D053454:Caspase 12; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014415:Tunicamycin
keywords: Apoptosis; Endoplasmic reticulum stress; Heart; Ischemia/reperfusion injury; Neuregulin-1