Key result
Intramyocardial Shh gene transfer plus AMD3100 improves post-MI LVEF recovery in mice vs either alone.
Why the study?
Sonic hedgehog gene transfer improves myocardial recovery after MI by enhancing progenitor cell incorporation, but it is unknown if AMD3100-induced progenitor-cell mobilization can further improve its effectiveness.
Does combination therapy with Shh gene transfer and AMD3100 improve cardiac functional recovery and neovascularization after myocardial infarction in mice?
Does combination therapy with Shh gene transfer and AMD3100 improve cardiac functional recovery and neovascularization after myocardial infarction in mice?
Combination therapy with intramyocardial Shh gene transfer and AMD3100-induced progenitor-cell mobilization synergistically improves cardiac functional recovery and neovascularization after myocardial infarction in a mouse model.
Objectives 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 upregulating 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 9 (MMP-9)–knockout mice, and in mice transplanted with bone marrow that expressed green-fluorescent protein. Mice were treated with 100 μg phShh (administered intramyocardially), 5 mg/kg 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, with greater capillary density and smooth-muscle–containing vessel density, and with 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.
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Roncalli et al. (2011) studied myocardial infarction. Shh gene transfer and AMD3100 combination therapy vs. phShh alone or AMD3100 alone was evaluated on cardiac functional recovery (left-ventricular ejection fraction). Combination therapy with intramyocardial Shh gene transfer and AMD3100 improved cardiac functional recovery after MI in mice, proving superior to either individual treatment.
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