title: The Paracrine Effect of Skeletal Myoblasts Is Cardioprotective Against Oxidative Stress and Involves EGFR-ErbB4 Signaling, Cystathionase, and the Unfolded Protein Response.
abstract: Therapeutic effects of skeletal myoblast transplantation into the myocardium are mediated via paracrine factors. We investigated the ability of myoblast-derived soluble mediators to protect cardiomyocytes from oxidative stress. Fetal rat cardiac cells were treated with conditioned medium from cultures of myoblasts or cardiac fibroblasts, and oxidative stress was induced with H2O2. Myoblast-derived factors effectively prevented oxidative stress-induced cardiac cell death and loss of mitochondrial membrane potential. This protective effect was mediated via epidermal growth factor (EGF) receptor and c-Met signaling, and mimicked by neuregulin 1 but not EGF. Microarray analysis of cardiac cells treated with myoblast versus cardiac fibroblast-derived mediators revealed differential regulation of genes associated with antioxidative effects: cystathionine-γ-lyase (cst), xanthine oxidase, and thioredoxin-interacting protein as well as tribbles homolog 3 (trib3). Cardiac cell pretreatment with tunicamycin, an inducer of trib3, also protected them against H2O2-induced cell death. Epicardial transplantation of myoblast sheets in a rat model of acute myocardial infarction was used to evaluate the expression of CST and trib3 as markers of myoblasts' paracrine effect in vivo. Myoblast sheets induced expression of the CST as well as trib3 in infarcted myocardium. CST localized around blood vessels, suggesting smooth muscle cell localization. Our results provide a deeper molecular insight into the therapeutic mechanisms of myoblast-derived paracrine signaling in cardiac cells and suggest that myoblast transplantation therapy may prevent oxidative stress-induced cardiac deterioration and progression of heart failure.
authors.affiliation: Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Siltanen
authors.forename: Kristo
authors.initials: K
authors.lastname: Nuutila
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Uenaka
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäkelä
authors.forename: Tommi
authors.initials: T
authors.lastname: Pätilä
authors.forename: Antti
authors.initials: A
authors.lastname: Vento
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Ari
authors.initials: A
authors.lastname: Harjula
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017208:Rats, Wistar; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C497110:Atf4 protein, rat; D002316:Cardiotonic Agents; D017077:Culture Media, Conditioned; C502443:Trib3 protein, rat; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D019859:Proto-Oncogene Proteins c-met; D066247:Receptor, ErbB-4; D017346:Protein Serine-Threonine Kinases; D003542:Cystathionine gamma-Lyase