Abstract
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.
Highlights
Angiogenesis is a complex multistep process of formation of new vessels that is regulated by several growth factors [1] (Fig. 1)
SGC inhibitors failed to block these effects of YC-1 on Hypoxia-inducible factor-1 (HIF-1), and further treatment with 8-bromo-cyclic guanosine monophosphate (cGMP) failed to inhibit the hypoxic induction of HIF-1. These results indicate that the HIF-1-inhibitory effect of YC-1 is unlikely to be mediated by soluble guanylyl cyclase (sGC)/cGMP signal transduction, rather that the YC-1 effect is probably achieved by a novel cellular process linked with the oxygensensing pathway [93]
Our findings indicate that YC-1 has conducted a “rescue operation” by executing the following assignments; [1] prevention and/or inhibition of pathological retinal NV; via the inhibition of HIF-1 and its downstream pro-angiogenic molecules; [2] concomitant promotion of retinal physiological RV; via the inhibition of inducible nitric oxide synthase (iNOS)
Summary
Angiogenesis is a complex multistep process of formation of new vessels that is regulated by several growth factors [1] (Fig. 1). HIF-1 plays a critical role by regulating genes, which are involved in angiogenesis [58] erythropoiesis [59], energy metabolism, glycolysis, and apoptotic and proliferative responses to ischemia and hypoxia [57] (Fig. 6).
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