TY - JOUR
T1 - Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization
AU - Roncalli, Jrme
AU - Renault, Marie Ange
AU - Tongers, Jrn
AU - Misener, Sol
AU - Thorne, Tina
AU - Kamide, Christine
AU - Jujo, Kentaro
AU - Tanaka, Toshikazu
AU - Ii, Masaaki
AU - Klyachko, Ekaterina
AU - Losordo, Douglas W.
N1 - Funding Information:
This work was supported in part by National Institutes of Health grants HL-53354 , HL-57516 , HL-77428 , HL-95874 , HL-80137 , and PO1HL-66957 . Dr. Roncalli was supported by the French Federation of Cardiology and Sanofi-Synthelabo Inc, Paris, France. The authors have reported that they have no relationships to disclose.
PY - 2011/6/14
Y1 - 2011/6/14
N2 - Objectives: 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 marrowderived 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 cellderived 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 musclecontaining 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.
AB - Objectives: 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 marrowderived 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 cellderived 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 musclecontaining 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.
KW - angiogenesis
KW - gene therapy
KW - myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=79958295157&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958295157&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2010.11.069
DO - 10.1016/j.jacc.2010.11.069
M3 - Article
C2 - 21658566
AN - SCOPUS:79958295157
SN - 0735-1097
VL - 57
SP - 2444
EP - 2452
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 24
ER -