Angiogenesis Is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1α/VP16 Hybrid Transcription Factor

Abstract

The HIF-1alpha/VP16 hybrid transcription factor is able to promote significant improvement in perfusion of an ischemic limb. These results confirm the feasibility of a novel approach for therapeutic angiogenesis in which neovascularization may be achieved indirectly by use of a transcriptional regulatory strategy.

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.…”

“…[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.…”

Expression of constitutively stable hybrid hypoxia-inducible factor-1α protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury

“…Ad2/HIF-1␣/ VP16, Ad2/GFP, and Ad2/CMVEV (empty adenoviral vector), which encode the HIF-1␣/VP16 hybrid, green fluorescent protein (GFP), and no transgene, respectively, were constructed as described previously (11,18). The HIF-1␣/VP16 hybrid was composed of the DNA-binding and dimerization domains from HIF-1␣ and the transactivation domain of HSV VP16 protein (34). The HIF-1␣/NF-B hybrid was constructed as HIF-1␣/VP16, except that the transactivation domain of human NF-B was used.…”

“…Indeed, several mediators and other cardioprotective genes including iNOS, HSP70, erythropoietin (EPO), and VEGF are also known hypoxia-responsive or HIF-1 target genes. Recently, we demonstrated (34,37) that expression of HIF-1␣/VP16, a constitutively stable hybrid of HIF-1␣ and herpes simplex virus (HSV) VP16 protein, mimics the angiogenic response to hypoxia in vitro and in vivo by inducing multiple growth factors. In human fetal cardiac cells, adenovirus-mediated expression of HIF-1␣/VP16 upregulated several known HIF-1-inducible genes, including VEGF, Glut-1, Glut-3, and glycolytic enzymes (18).…”

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

“…30 Gene transfer of the HIF-1a/VP16 hybrid in a rabbit model of hind limb ischemia was associated with increased regional blood flow and capillary density. 31 In a rat model of acute myocardial ischemia, intramyocardial delivery of the HIF-1a/VP16 hybrid plasmid was able to reduce the size of myocardial infarction and increase capillary density in the border zone of the infarct area. The induction of angiogenesis was similar to the neovascularization that resulted from VEGF therapy by plasmid gene transfer in the same model.…”