title: GATA-4 protects against hypoxia-induced cardiomyocyte injury: effects on mitochondrial membrane potential.
abstract: Our previous studies have suggested that GATA-4 increases the differentiation of bone-marrow-derived mesenchymal stem cells (MSCs) into cardiac phenotypes. This study further investigated whether GATA-4 enhances MSC-mediated cardioprotection following hypoxia. MSCs were harvested from rat bone marrow and transduced with GATA-4 (MSC(GATA-4)). To mimic ischemic injury, cultured cardiomyocytes (CMs) isolated from neonatal rat ventricles were exposed to hypoxia or were pretreated with concentrated conditioned medium (CdM) from MSC(GATA-4) or transduced control MSC (MSC(Null)) for 16 h before exposure to hypoxic culture conditions (low glucose and low oxygen). Myocyte damage was estimated by annexin-V-PE and TUNEL technique and by lactate dehydrogenase (LDH) release. Cell survival was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) uptake. Mitochondrial membrane potential was determined using confocal microscopy. ELISA studies indicated that insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) were significantly increased in MSC(GATA-4) compared with MSC(Null). Hypoxia-induced apoptosis/cell death was significantly reduced when CMs were co-cultured with MSC(GATA-4) in a dual-chamber system. Cell protection mediated by MSC(GATA-4) was mimicked by treating CMs with CdM from MSC(GATA-4) and abrogated with IGF-1- and VEGF-neutralizing antibodies. MSC(GATA-4) protects CMs under hypoxic conditions. The release of IGF-1 and VEGF from MSC(GATA-4) is likely to be responsible for protection of CMs.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Li
authors.forename: Ya-Feng
authors.initials: YF
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D005269:Femur / Q000166:cytology; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000166:cytology; D014161:Transduction, Genetic; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D050991:GATA4 Transcription Factor; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I
keywords: GATA-4; apoptose; apoptosis; cardioprotection; cellules souches mésenchymateuses; conditioned media; facteurs paracrines; hypoxia; hypoxie; mesenchymal stem cell; milieu conditionné; mitochondrial membrane potential; paracrine factors; potentiel membranaire mitochondrial