Combined Gene Therapy with Hypoxia-Inducible Factor-1α and Heme Oxygenase-1 for Therapeutic Angiogenesis

• Published in: Tissue engineering. Part A Vol. 17; no. 7-8; pp. 915 - 926
• Main Authors: Bhang, Suk Ho, Kim, Ju Hee, Yang, Hee Seok, La, Wan-Geun, Lee, Tae-Jin, Kim, Ga Hee, Kim, Hyun Ah, Lee, Minhyung, Kim, Byung-Soo
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.04.2011
• Subjects: Animals; Apoptosis - genetics; Apoptosis - physiology; Blotting, Western; Care and treatment; Gene therapy; Genetic aspects; Genetic Therapy - methods; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hemoproteins; Hindlimb - blood supply; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Ischemia; Methods; Mice; Neovascularization; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - therapy; Original Articles; Properties; Reverse Transcriptase Polymerase Chain Reaction; South Korea
• ISSN: 1937-3341; 1937-335X
• DOI: 10.1089/ten.tea.2010.0493

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.