Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization

Jrme Roncalli; Marie Ange Renault; Jrn Tongers; Sol Misener; Tina Thorne; Christine Kamide; Kentaro Jujo; Toshikazu Tanaka; Masaaki Ii; Ekaterina Klyachko; Douglas W. Losordo

doi:10.1016/j.jacc.2010.11.069

Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization

Jrme Roncalli, Marie Ange Renault, Jrn Tongers, Sol Misener, Tina Thorne, Christine Kamide, Kentaro Jujo, Toshikazu Tanaka, Masaaki Ii, Ekaterina Klyachko, Douglas W. Losordo

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2444-2452
Number of pages	9
Journal	Journal of the American College of Cardiology
Volume	57
Issue number	24
DOIs	https://doi.org/10.1016/j.jacc.2010.11.069
State	Published - Jun 14 2011

Funding

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.

Keywords

angiogenesis
gene therapy
myocardial infarction

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2010.11.069

Cite this

Roncalli, J., Renault, M. A., Tongers, J., Misener, S., Thorne, T., Kamide, C., Jujo, K., Tanaka, T., Ii, M., Klyachko, E., & Losordo, D. W. (2011). Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization. Journal of the American College of Cardiology, 57(24), 2444-2452. https://doi.org/10.1016/j.jacc.2010.11.069

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title = "Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization",

abstract = "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.",

keywords = "angiogenesis, gene therapy, myocardial infarction",

author = "Jrme Roncalli and Renault, {Marie Ange} and Jrn Tongers and Sol Misener and Tina Thorne and Christine Kamide and Kentaro Jujo and Toshikazu Tanaka and Masaaki Ii and Ekaterina Klyachko and Losordo, {Douglas W.}",

note = "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. ",

year = "2011",

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day = "14",

doi = "10.1016/j.jacc.2010.11.069",

language = "English (US)",

volume = "57",

pages = "2444--2452",

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Roncalli, J, Renault, MA, Tongers, J, Misener, S, Thorne, T, Kamide, C, Jujo, K, Tanaka, T, Ii, M, Klyachko, E & Losordo, DW 2011, 'Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization', Journal of the American College of Cardiology, vol. 57, no. 24, pp. 2444-2452. https://doi.org/10.1016/j.jacc.2010.11.069

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

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ER -

Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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