Inhibition of oxygen-induced ischemic retinal neovascularization with adenoviral 15-lipoxygenase-1 gene transfer via up-regulation of PPAR-γ and down-regulation of VEGFR-2 expression.
15-lipoxygenase-1 (15-LOX-1) plays an important role in angiogenesis, but how it works still remains a controversial subject. The aims of our study are focused on determining whether or not 15-LOX-1 inhibiting oxygen-induced ischemic retinal neovascularization (RNV) and the underlying regulatory mechanism involving of 15-LOX-1, peroxisome proliferator-activated receptor γ (PPAR-γ) and vascular endothelial growth factor receptor 2 (VEGFR-2) in oxygen-induced retinopathy (OIR). Recombinant adenoviral vectors that expressing the 15-LOX-1 gene (Ad-15-LOX-1-GFP) or the green fluorescence protein gene (Ad-GFP) were intravitreous injected into the OIR mice at postnatal day 12 (P12), the mice were sacrificed 5 days later (P17). Retinal 15-LOX-1 expression was significantly increased at both mRNA and protein levels after 15-LOX-1 gene transfer. Immunofluorescence staining of retinal sections revealed 15-LOX-1 expression was primarily in the outer plexiform layer (OPL), inner nuclear layer (INL) and ganglion cell layer (GCL) retina. Meanwhile, RNV was significantly inhibited indicated by fluorescein retinal angiography and quantification of the pre-retinal neovascular cells. The expression levels of PPAR-γ were significantly up-regulated while VEGFR-2 were significantly down-regulated both in mRNA and protein levels. Our results suggested 15-LOX-1 gene transfer inhibited RNV in OIR mouse model via up-regulation of PPAR-γ and further down-regulation of VEGFR-2 expression. This could be a potentially important regulatory mechanism involving 15-LOX-1, PPAR-γ and VEGFR-2 during RNV in OIR. In conclusion, 15-LOX-1 may be a new therapeutic target for treating neovascularization diseases.
Eye Center, Renmin Hospital of Wuhan University, Eye Institute of Wuhan University, Wuhan, Hubei, China ; Department of Ophthalmology, Hospital Affiliated to Hubei University of Arts and Science, Xiangyang Central Hospital, Xiangyang, Hubei, China.
Zhi
Z
Li
Eye Center, Renmin Hospital of Wuhan University, Eye Institute of Wuhan University, Wuhan, Hubei, China.
Tao
T
He
Department of Oncology, Hospital Affiliated to Hubei University of Arts and Science, Xiangyang Central Hospital, Xiangyang, Hubei, China.
Ke
K
Du
Eye Center, Renmin Hospital of Wuhan University, Eye Institute of Wuhan University, Wuhan, Hubei, China.
Yi-Qiao
YQ
Xing
Clinical Laboratory, Hospital Affiliated to Hubei University of Arts and Science, Xiangyang Central Hospital, Xiangyang, Hubei, China.
Yuan-Min
YM
Run
Department of Ophthalmology, Wuhan General Hospital of Guangzhou Military, Wuhan, Hubei, China.
Ying
Y
Yan
Eye Center, Renmin Hospital of Wuhan University, Eye Institute of Wuhan University, Wuhan, Hubei, China.
Yin
Y
Shen
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015854:Up-Regulation / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
D047495:PPAR gamma; D001093:Arachidonate 15-Lipoxygenase; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen