Pleiotropic Effects of YC-1 Selectively Inhibit Pathological Retinal Neovascularization and Promote Physiological Revascularization in a Mouse Model of Oxygen-Induced Retinopathy

被引:40
作者
DeNiro, M. [1 ,3 ]
Al-Halafi, A. [2 ]
Al-Mohanna, F. H. [3 ]
Alsmadi, O. [4 ]
Al-Mohanna, F. A. [5 ]
机构
[1] King Khalid Eye Specialist Hosp, Res Dept, Riyadh 11462, Saudi Arabia
[2] King Khalid Eye Specialist Hosp, Vitreoretinal Div, Riyadh 11462, Saudi Arabia
[3] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Res Ctr, Riyadh 11211, Saudi Arabia
[4] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Res Ctr, Riyadh 11211, Saudi Arabia
[5] King Faisal Specialist Hosp & Res Ctr, Dept Biol & Med Res, Riyadh 11211, Saudi Arabia
关键词
ENDOTHELIAL GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; PROLIFERATIVE DIABETIC-RETINOPATHY; HYPOXIA-INDUCIBLE FACTOR-1; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; MONOCYTE CHEMOTACTIC PROTEIN-1; CHOROIDAL NEOVASCULARIZATION; MATRIX METALLOPROTEINASES; GUANYLATE-CYCLASE; GENE-EXPRESSION;
D O I
10.1124/mol.109.061366
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Vascular endothelial growth factor (VEGF) and inducible nitric-oxide synthase (iNOS) have been implicated in ischemia-induced retinal neovascularization. Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina is the inhibition of angiogenesis. Furthermore, iNOS was shown to be overexpressed in Muller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of hypoxia-inducible factor (HIF)-1 alpha, has been shown to inhibit iNOS expression in various tissue models. Our aim was to assess the pleiotropic effects of YC-1 in an oxygen-induced retinopathy (OIR) mouse model and evaluate its therapeutic potential in HIF-1- and iNOS-mediated retinal pathologies. Dual-injections of YC-1 into the neovascular retinas decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, and concomitantly promoted physiological retinal revascularization, compared with dimethyl sulfoxide (DMSO)-treated group. Furthermore, YC-1-treated retinas exhibited a marked increase in immunoreactivities for CD31 and von Willebrand factor and displayed significant inhibition in HIF-1 alpha protein expression. Furthermore, YC-1 down-regulated VEGF, erythropoietin, endothelin-1, matrix metalloproteinase-9, and iNOS message and protein levels. When hypoxic Muller and neuoroglial cells were treated with YC-1, iNOS mRNA and protein levels were reduced in a dose-dependent fashion. We demonstrate that YC-1 inhibits pathological retinal neovascularization by exhibiting antineovascular activities, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. Furthermore, YC-1 enhanced physiological revascularization of the retinal vascular plexuses via the inhibition of iNOS mRNA and protein expressions. The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization.
引用
收藏
页码:348 / 367
页数:20
相关论文
共 97 条
[1]   Inducible nitric oxide synthase and vascular endothelial growth factor are colocalized in the retinas of human subjects with diabetes [J].
Abu El-Asrar, AM ;
Meersschaert, A ;
Dralands, L ;
Missotten, L ;
Geboes, K .
EYE, 2004, 18 (03) :306-313
[2]   Monocyte chemotactic protein-1 in proliferative vitreoretinal disorders [J].
AbuElAsrar, AM ;
VanDamme, J ;
Put, W ;
Veckeneer, M ;
Dralands, L ;
Billiau, A ;
Missotten, L .
AMERICAN JOURNAL OF OPHTHALMOLOGY, 1997, 123 (05) :599-606
[3]   Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia [J].
Adachi, K ;
Kashii, S ;
Masai, H ;
Ueda, M ;
Morizane, C ;
Kaneda, K ;
Kume, T ;
Akaike, A ;
Honda, Y .
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 1998, 236 (10) :766-774
[4]   VASCULAR ENDOTHELIAL GROWTH-FACTOR ACTS AS A SURVIVAL FACTOR FOR NEWLY FORMED RETINAL-VESSELS AND HAS IMPLICATIONS FOR RETINOPATHY OF PREMATURITY [J].
ALON, T ;
HEMO, I ;
ITIN, A ;
PEER, J ;
STONE, J ;
KESHET, E .
NATURE MEDICINE, 1995, 1 (10) :1024-1028
[5]   ARTERIAL OXYGEN TENSION AND RETINAL VASOCONSTRICTION IN NEWBORN INFANTS [J].
ARANDA, JV ;
SAHEB, N ;
STERN, L ;
AVERY, ME .
AMERICAN JOURNAL OF DISEASES OF CHILDREN, 1971, 122 (03) :189-&
[6]   SHEDDING LIGHT ON BLINDNESS [J].
BARINAGA, M .
SCIENCE, 1995, 267 (5197) :452-453
[7]   Correlations between neuronal nitric oxide synthase and muscarinic M3/M1 receptors in the rat retina [J].
Borda, E ;
Berra, A ;
Saravia, M ;
Ganzinelli, S ;
Sterin-Borda, L .
EXPERIMENTAL EYE RESEARCH, 2005, 80 (03) :391-399
[8]  
Brooks SE, 2001, INVEST OPHTH VIS SCI, V42, P222
[9]  
Campochiaro PA, 2000, J CELL PHYSIOL, V184, P301, DOI 10.1002/1097-4652(200009)184:3<301::AID-JCP3>3.0.CO
[10]  
2-H