Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury

• Published in: Peptides (New York, N.Y. : 1980) Vol. 88; pp. 196 - 207
• Main Authors: Fang, Shan-Juan, Li, Peng-Yang, Wang, Chun-Mei, Xin, Yi, Lu, Wei-Wei, Zhang, Xiao-Xia, Zuo, Song, Ma, Chang-Sheng, Tang, Chao-Shu, Nie, Shao-Ping, Qi, Yong-Fen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Cardiotonic Agents - administration & dosage; Caspase 12 - genetics; CCAAT-Enhancer-Binding Proteins - genetics; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Heart; Heat-Shock Proteins - genetics; Humans; Ischemia/reperfusion injury; Myocardial Infarction - chemically induced; Myocardial Infarction - drug therapy; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocardial Reperfusion Injury - chemically induced; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - pathology; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neuregulin-1; Neuregulin-1 - administration & dosage; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins c-akt - genetics; Rats; Signal Transduction - drug effects; Tunicamycin - toxicity; Heart; Ischemia/reperfusion injury; DTT; H/R; LV; I/R; Endoplasmic reticulum stress; SD; DMEM; Neuregulin-1; TUNEL; IA/AA; NRG-1; FBS; Tm; CHOP; NRVM; CM; siRNA; Bcl; AA/LV; ER; LAD; ARVM; P13K; ERK; Apoptosis
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2016.12.009

•NRG-1 inhibits cardiomyocyte ER stress induced by tunicamycin and dithiothreitol.•NRG-1 inhibits cardiomyocyte ER stress through ErbB4 receptor.•The inhibitory effects of NRG-1 on cardiomyocyte ER stress is through PI3K/Akt signaling pathway.•NRG-1 attenuates apoptosis and ER stress induced by H/R in cardiomyocytes.•NRG-1 reduces the myocardial I/R injury and ER stress in I/R heart. 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.