Combined gene therapy with hypoxia-inducible factor-1α and heme oxygenase-1 for therapeutic angiogenesis.
Transfection with either hypoxia-inducible factor-1α (HIF-1α) or heme oxygenase-1 (HO-1) gene can induce neovascularization in ischemic tissues. Although expression of transfected HIF-1α gene occurs rapidly, the expressed HIF-1α protein degrades quickly, limiting its therapeutic efficacy. Meanwhile, expressed HO-1 protein does not rapidly undergo degradation, but gene expression occurs a couple of days after transfection, resulting in apoptosis and a delay in angiogenesis in ischemic tissues at the incipient period of HO-1 gene transfection. We hypothesize that combined delivery of HIF-1α and HO-1 gene will enhance antiapoptosis and neovascularization in ischemic tissue compared with HIF-1α or HO-1 single-gene therapy. To test this hypothesis, ischemic mouse hindlimbs were treated with HIF-1α and/or HO-1 gene therapy. The combined gene therapy proved superior to both single-gene therapies, resulting in rapid expression of HIF-1α gene and long-term maintenance of expressed HO-1 protein. The apoptosis in the ischemic region was significantly less, and angiogenic growth factor secretion and angiogenesis were greater in the combined gene therapy than in either of the single-gene therapies. Our results suggest that a combined gene therapy of HIF-1α and HO-1 enhances the transfection of both genes and improves angiogenesis compared with either single-gene therapy.
Bhang
Suk Ho
SH
School of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea.
Kim
Ju Hee
JH
Yang
Hee Seok
HS
La
Wan-Geun
WG
Lee
Tae-Jin
TJ
Kim
Ga Hee
GH
Kim
Hyun Ah
HA
Lee
Minhyung
M
Kim
Byung-Soo
BS
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D015316:Genetic Therapy / Q000379:methods*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007511:Ischemia; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051547:Heme Oxygenase-1