Intravitreal adenoviral 15-lipoxygenase-1 gene transfer prevents vascular endothelial growth factor A-induced neovascularization in rabbit eyes.
Excessive angiogenesis mediated by vascular endothelial growth factor (VEGF) plays an important role in angioproliferative ocular diseases. We have previously developed a large animal model for these diseases by intravitreal adenoviral gene transfer of VEGF-A(165). 15-Lipoxygenase-1 (15-LO-1), an oxidizing enzyme producing reactive lipid hydroperoxides, has been shown to induce aberrant angiogenesis in cancer models of transgenic mice overexpressing human 15-LO-1. Our purpose was to study the effects of 15-LO-1 on VEGF-A(165)-induced angiogenesis in New Zealand White rabbit eyes, using intravitreal adenovirus-mediated gene transfers. AdCMV and Adh15-LO-1 alone served as controls. As determined by immunohistochemistry, VEGF-A(165) significantly increased the number and size of the capillaries in various compartments of the eyes. 15-LO-1 efficiently inhibited VEGF-A(165)-induced neovascularization and pathological changes by reducing VEGF-A(165) mRNA and protein expression, determined by RT-PCR, ELISA, and immunohistochemistry. 15-LO-1, which produces endogenous ligands for peroxisome proliferator-activated receptor-gamma (PPARgamma), also prevented VEGF-A(165)-induced expression of PPARgamma and VEGF receptor-2, as measured by quantitative RT-PCR. In conclusion, our findings show that 15-LO-1 prevents VEGF-A(165)-induced angiogenesis and consequent pathology in the eyes, suggesting that intravitreal 15-LO-1 gene transfer could be a potential new strategy for the treatment of neovascular complications in the eyes.
Viita
Helena
H
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland.
Kinnunen
Kati
K
Eriksson
Emmi
E
Lähteenvuo
Johanna
J
Babu
Mohan
M
Kalesnykas
Giedrius
G
Heikura
Tommi
T
Laidinen
Svetlana
S
Takalo
Teemu
T
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008024:Ligands; D008268:Macular Degeneration / Q000628:therapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000517:prevention & control*; D009898:Optic Disk / Q000098:blood supply / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D011817:Rabbits; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2
D008024:Ligands; D047495:PPAR gamma; D042461:Vascular Endothelial Growth Factor A; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D040301:Vascular Endothelial Growth Factor Receptor-2