title: β1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response.
abstract: β(1)-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. β(1)-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated β(1)-integrin expression. Hypertrophy was induced in neonatal cardiomyocytes by endothelin-1 (ET-1), which activated the regulatory NADPH oxidase subunit Rac1, evoked ROS, and enhanced fetal gene expression and cardiomyocyte size. ET-1 also enhanced cell adhesion and FAK phosphorylation and inhibited oxidative stress-induced cardiomyocyte apoptosis. Further, ET-1 increased β(1)-integrin mRNA and protein expression via Rac1-ROS-dependent MEK/ERK and EGF receptor-PI3K/Akt activation as shown by adenoviral dominant-negative Rac1 or overexpression of copper/zinc-superoxide dismutase. The relevance of regulated β(1)-integrin expression was examined in cardiomyocytes, in which targeting siRNA impeded the ET-1-induced β(1)-integrin up-regulation. In these cells, ET-1-induced cell adhesion, FAK phosphorylation, and hypertrophic response were significantly blunted, whereas its antiapoptotic effect was predominantly unchanged, suggesting at least partial dissociation of prohypertrophic and prosurvival signaling elicited by ET-1. In conclusion, β(1)-integrin up-regulation in response to ET-1 is mediated via Rac1-ROS-dependent activation of prohypertrophic pathways and is mandatory for ET-1-induced FAK activation, cell adhesion, and hypertrophic response.
authors.affiliation: Myocardial Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Stéphanie P
authors.initials: SP
authors.lastname: Häuselmann
authors.forename: Berit I
authors.initials: BI
authors.lastname: Rosc-Schlüter
authors.forename: Vera
authors.initials: V
authors.lastname: Lorenz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plaisance
authors.forename: Marijke
authors.initials: M
authors.lastname: Brink
authors.forename: Otmar
authors.initials: O
authors.lastname: Pfister
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Kuster
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D019012:Integrin beta1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein