title: Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization.
abstract: OBJECTIVE
  This study was designed to compare the effectiveness of Sonic hedgehog (Shh) gene transfer, AMD3100-induced progenitor-cell mobilization, and Shh-AMD3100 combination therapy for treatment of surgically induced myocardial infarction (MI) in mice.
  
  
  BACKGROUND
  Shh gene transfer improves myocardial recovery by up-regulating angiogenic genes and enhancing the incorporation of bone marrow-derived progenitor cells (BMPCs) in infarcted myocardium. Here, we investigated whether the effectiveness of Shh gene therapy could be improved with AMD3100-induced progenitor-cell mobilization.
  
  
  METHODS
  Gene expression and cell function were evaluated in cells cultured with medium collected from fibroblasts transfected with plasmids encoding human Shh (phShh). MI was induced in wild-type mice, in matrix metalloproteinase (MMP)-9 knockout mice, and in mice transplanted with bone marrow that expressed green-fluorescent protein. Mice were treated with 100 μg of phShh (administered intramyocardially), 5 mg/kg of AMD3100 (administered subcutaneously), or both; cardiac function was evaluated echocardiographically, and fibrosis, capillary density, and BMPC incorporation were evaluated immunohistochemically.
  
  
  RESULTS
  phShh increased vascular endothelial growth factor and stromal cell-derived factor 1 expression in fibroblasts; the medium from phShh-transfected fibroblasts increased endothelial-cell migration and the migration, proliferation, and tube formation of BMPCs. Combination therapy enhanced cardiac functional recovery (i.e., left ventricular ejection fraction) in wild-type mice, but not in MMP-9 knockout mice, and was associated with less fibrosis, greater capillary density and smooth muscle-containing vessel density, and enhanced BMPC incorporation.
  
  
  CONCLUSIONS
  Combination therapy consisting of intramyocardial Shh gene transfer and AMD3100-induced progenitor-cell mobilization improves cardiac functional recovery after MI and is superior to either individual treatment for promoting therapeutic neovascularization.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roncalli
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.forename: Jörn
authors.initials: J
authors.lastname: Tongers
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Christine
authors.initials: C
authors.lastname: Kamide
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jujo
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D001596:Benzylamines; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D000080027:Cyclams; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D053823:Hedgehog Proteins / Q000008:administration & dosage*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D013234:Stem Cells / Q000378:metabolism*; D015996:Survival Rate; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D053823:Hedgehog Proteins; D006571:Heterocyclic Compounds; C465570:Shh protein, mouse; C088327:plerixafor