title: Attenuation of cardiac hypertrophy by G-CSF is associated with enhanced migration of bone marrow-derived cells.
abstract: Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 μg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4(+) and c-kit(+) BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4(+) and c-kit(+) BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.
authors.affiliation: Medical Department I, Campus Grosshadern and Campus Innenstadt, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Huber
authors.forename: Nick L
authors.initials: NL
authors.lastname: Beetz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Laskowski
authors.forename: Tilman
authors.initials: T
authors.lastname: Ziegler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grabmaier
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064752:Atrial Remodeling / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects*; D006332:Cardiomegaly / Q000503:physiopathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis / Q000517:prevention & control; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019089:Stem Cell Factor; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor
keywords: BMCs; G-CSF; fibrosis; hypertrophy; migration