Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis

DeNiro, Michael; Alsmadi, Osama; Almohanna, Falah

doi:10.1016/j.exer.2009.06.013

Cited by 33 publications

(36 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous investigation (DeNiro et al, 2009), we demonstrated that YC-1 possesses several antiangiogenic properties, both in vitro and ex vivo, which could be exploited as valuable therapeutic potentials to inhibit the formation and growth of new retinal vessels in the hypoxic retina. Previous data have indicated that YC-1 inhibits experimental choroidal NV in rats (Song et al, 2008).…”

Section: Suppression Of Pathologic Retinal Neovascularization By Yc-1mentioning

confidence: 99%

“…In platelets and vascular smooth muscle, the administration of YC-1 is accompanied by an increase in the intracellular cGMP concentration, which occurs via the stimulation of sGC (Teng et al, 1997;Galle et al, 1999). We have recently demonstrated that YC-1 down-regulates HIF-1␣, HIF-2␣, VEGF, EPO, ET-1, and MMP-9 protein levels in the human retinal microvascular endothelial cells (DeNiro et al, 2009). During this study, we hypothesized the following: 1) YC-1 possesses novel pleiotropic effects, which could impair ischemia-induced expression of HIF-1 and its downstream angiogenic molecules.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

DeNiro¹,

Al-Halafi²,

Almohanna³

et al. 2009

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF) and inducible nitricoxide 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 Mü ller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of hypoxia-inducible factor (HIF)-1␣, 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␣ protein expression. Furthermore, YC-1 down-regulated VEGF, erythropoietin, endothelin-1, matrix metalloproteinase-9, and iNOS message and protein levels. When hypoxic Mü ller and neuoroglial cells were treated with YC-1, iNOS mRNA and protein levels were reduced in a dosedependent 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.Retinal neovascularization (NV) is the major cause of severe vision loss and irreversible blindness in developed countries, affecting people of all ages (Lee et al., 1998). These clinical and pathologic manifestations occur in diabetic retinopathy, retinopathy of prematurity (ROP), age-related macular degeneration and retinal vein occlusion. The early stages of retinopathy result from retinal ischemia as a result of nonperfusion of the retina or a decrease in oxygen tension (Barinapa, 1995). In the late stages, the ischemia-induced pathologic growth of new blood vessels can cause catastrophic loss of vision.

show abstract

Section: Suppression Of Pathologic Retinal Neovascularization By Yc-1mentioning

confidence: 99%

mentioning

confidence: 99%

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

DeNiro¹,

Al-Halafi²,

Almohanna³

et al. 2009

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…4F, n ϭ 8). These genes included Hif1␣, Has2, and VEGF-B, which play important roles in retinal neovascularization (25,42,43). Furthermore, upon PDGF-D knockdown, the expression of many proapoptotic genes in the neovascular retina was increased at different time points (Fig.…”

Section: Pdgf-dd Inhibition Suppresses Retinalmentioning

confidence: 96%

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Kumar

Lee

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3␤ (GSK3␤) Ser 9 phosphorylation and Tyr 216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3␤ activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3␤ and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

show abstract

“…Recently, we have demonstrated that YC-1 suppressed vascular endothelial cell proliferation, migration and tube formation, while it significantly increased the proteasome activity [94,95]. These data revealed that YC-1 possesses pleiotropic effects, which target several anti-angiogenic mechanisms in the retinal cell model and the retinal explant culture setting.…”

Section: Anti-hif-1 Anti-angiogenic and Anti-neovascular Effects Ofmentioning

confidence: 98%

Dual Targeting of Retinal Vasculature in the Mouse Model of Oxygen Induced Retinopathy

DeNiro¹

2011

TODIAJ

View full text Add to dashboard Cite

Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in retinal neovascularization (NV) by upregulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating retinal angiopathies. Many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting agents, which could be utilized in the treatment of several ocular pathologies. This review focuses on the potential of HIF-1 as a target molecule for the treatment of retinal NV, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti-HIF-1, anti-neovascular agent in the retinal model. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in retinal microvascular endothelial cells. Moreover, it inhibited retinal NV in the oxygen-induced retinopathy (OIR) mouse model without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anti-neovascular agents that could be used in the retinal pathologies.

show abstract

Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis

Cited by 33 publications

References 64 publications

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

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

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Dual Targeting of Retinal Vasculature in the Mouse Model of Oxygen Induced Retinopathy

Contact Info

Product

Resources

About