title: Neuregulin-1 protects against doxorubicin-induced apoptosis in cardiomyocytes through an Akt-dependent pathway.
abstract: In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown. In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed. Neonatal rat ventricular myocytes (NRVMs) were subjected to various treatments, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining). The activation of Akt was detected by means of western blot analysis. The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ratio of Bcl-2/Bax. However, all of these effects were markedly antagonized by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process. RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium.
authors.affiliation: Heart Failure Center, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: An
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Yin
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Zou
authors.forename: B
authors.initials: B
authors.lastname: Wei
authors.forename: R
authors.initials: R
authors.lastname: Lv
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C094131:NRG1 protein, human; D020890:Neuregulin-1; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt