Combined delivery of heme oxygenase-1 gene and fibroblast growth factor-2 protein for therapeutic angiogenesis.
Ectopic expression of heme oxygenase-1 (HO-1) in ischemic tissue protects the tissue from apoptosis and necrosis and promotes angiogenesis. However, apoptosis and necrosis will decrease HO-1 gene transfection efficacy. We hypothesized that fibroblast growth factor-2 (FGF2) would attenuate ischemic damage during the incipient period, improve HO-1 gene transfection and, in turn, enhance neovascularization. To test this hypothesis, we employed a mouse model of hindlimb ischemia and treated the mice with HO-1 gene therapy alone, FGF2 alone, or HO-1 gene therapy plus FGF2. As controls, a group of mice was left untreated. At 12h, prior to the expression of exogenously delivered HO-1, apoptosis was significantly reduced in mice treated with FGF2, either alone or in combination with HO-1 gene therapy. At 3 days, HO-1 expression was greater in mice that also received FGF2 than in mice treated with HO-1 gene therapy alone. The expression of angiogenic growth factors and angiogenesis was greater in mice treated with HO-1 gene therapy plus FGF2 than in mice treated with HO-1 gene therapy alone. These data indicate that FGF2 rescued muscle necrosis prior to the exogenous expression of HO-1 and enhanced HO-1 gene transfection in ischemic murine limbs.
Bhang
Suk H
SH
School of Chemical and Biological Engineering, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-744, Republic of Korea.
Kim
Ju H
JH
Yang
Hee S
HS
La
Wan-Geun
WG
Lee
Tae-Jin
TJ
Sun
Ah-Young
AY
Kim
Ga H
GH
Lee
Minhyung
M
Kim
Byung-Soo
BS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006614:Hindlimb / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016222:Fibroblast Growth Factor 2; D051547:Heme Oxygenase-1