Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets

Abstract

The feasibility of a novel therapeutic strategy using angiogenic growth factors to expedite and/or augment collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors whose mitogenic activity on endothelial cells is very potent. Although it has been demonstrated that HGF is a potential angiogenic growth factor in in vitro culture systems, there is no direct in vivo evidence for the angiogenic activity of HGF in physiological conditions. In this study, we hypothesized that transfection of HGF gene into infarcted myocardium could induce angiogenesis, potentially resulting in a beneficial response to hypoxia. Human HGF gene or control vector driven by the SR␣ promoter was transfected into rat myocardium by the HVJ-liposome method. Four days after in vivo transfection of human HGF gene, there was a marked increase in human immunoreactive HGF as compared with control vector (P Ͻ 0.01). In myocardium transfected with HGF vector, a significant increase in PCNA-positive endothelial cells was observed, while few PCNA-positive endothelial cells were detected in both control-vector-transfected and untreated myocardium. The number of vessels around

Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle

“…[4][5][6][7][8][9][10][11] Instead of VEGF, other angiogenic growth factors such FGF, HGF and a transcription factor for angiogenesis, HIF (hypoxiainducible factor), have been considered candidates for therapeutic angiogenesis as gene therapy for the treatment of patients with critical limb ischemia. [12][13][14][15][16][17][18][19][20] Although the feasibility of therapeutic angiogenesis using these angiogenic growth factors has been reported in experimental models and human clinical trials, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] there are still unresolved problems such as undesirable side-effects. Most clinical trials have employed intramuscular injection of naked plasmid DNA despite its low transfection efficiency.…”

“…12,18 This promoter/enhancer has been used to express reporter genes in a variety of cell types and can be considered to be constitutive. Downstream from the HGF cDNA is the SV40 polyadenylation sequence.…”

“…[8][9][10][11] In addition to VEGF, the utility of gene transfer of other angiogenic growth factors such as fibroblast growth factor (FGF) or hepatocyte growth factor (HGF) has been reported to stimulate collateral formation. [12][13][14][15][16][17][18][19][20] The feasibility of gene therapy using angiogenic growth factors to treat peripheral arterial disease seems to be superior to recombinant protein therapy for the following reasons: (1) It has the potential to maintain an optimally high and local concentration over time. This issue may be critical in the case of arterial gene therapy.…”

Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia

“…Transfer of HGF with the hemagglutinating virus of Japan (HVJ)-liposome method has been shown to induce angiogenesis in normal and infarcted myocardium. 15 Cell-based gene transfer is a novel strategy that utilizes autologous cells as vectors after in vitro transfection with a transgene of interest. 16 Such a system is able to circumvent the inflammatory response by using autologous cells and achieves prolonged expression by stable transfection using various measures including electroporation and in vitro retroviral or lentiviral transfection.…”

Gene therapy for preventing neuronal death using hepatocyte growth factor: in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons

“…24 This promoter/ enhancer has been used to express reporter genes in a variety of cell types and can be considered to be constitutive. Downstream from the HGF cDNA is the SV40 polyadenylation sequence.…”