TAK1 blockade as a therapy for retinal neovascularization

Abstract

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Pathological angiogenesis occurs through the complex activation of pro-inflammatory and pro-angiogenic pathways. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1). TAK1 is a key mediator of inflammation, innate immune responses, apoptosis and tissue homeostasis and plays an important role in physiological angiogenesis. Its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. We investigated the regulatory role of TAK1 in pathological angiogenesis in the retina. Transcriptome analysis of human retina featuring retinal neovascularization revealed enrichment of known TAK1-mediated signaling pathways. Genetic or pharmacological inhibition of TAK1 activation in human endothelial cells induced by TNFα or IL-1 stimulation led to inhibition of phosphorylation of major kinases, including nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (MAPK) signaling pathways. Suppression of this signaling, in turn, decreased expression of downstream genes associated with inflammation and angiogenesis, suggesting that TAK1 is required for these pathological processes. Transcriptome analysis of endothelial cells revealed that TAK1 knockout prevented inflammatory and immune responses induced by TNFα stimulation, mainly via cytokine and chemokine activity. Selective inhibition of TAK1 by 5Z-7-oxozeaenol in vitro ameliorated pro-angiogenic activity, including endothelial cell proliferation, migration and tube formation. Moreover, 5Z-7-oxozeaenol attenuated aberrant retinal angiogenesis in rats following oxygen-induced retinopathy. Our finding shows that TAK1 plays a key role in pathological angiogenesis in the retina. Selective inhibition of TAK1 prevents pathological angiogenesis, suggesting that TAK1 could be a potential therapeutic target for retinal neovascularization.GRAPHICAL ABSTRACT

Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization

“…Inflammation obviously comprises the pathologic process of CoNV, but inflammation-targeting therapies may not be ideal in treating CoNV. Although 5Z-7-oxozeaenol and GNPs-Oxo did not show anti-inflammatory effects as observed in other animal models, such as cerebral ischemia, arthritis, and retinal angiogenesis [18,29,62], we provide evidence that GNPs-Oxo is a approach to produce significant anti-angiogenic effect against chemical cauterization-induced CoNV in vivo. Moreover, to further manage the inflammatory response, combination therapy with steroids may be an attractive approach that can have an additive effect on the treatment of CoNV.…”

“…TAK1 as a potential therapeutic target for pathologic angiogenesis has been widely studied as it closely engages in several important angiogenic activities, such as inflammatory response, hypoxia, and oxidative stress [42]. Indeed, our previous study showed that TAK1 inhibition by 5Z-7-oxozeaenol effectively prevents retinal neovascularization [18], suggesting that the approach can be applied to other ocular neovascularization, such as CoNV. Conventional methods of drug delivery to cornea mainly rely on application of eye drops, an effective approach though with many limitations, such as poor ocular drug bioavailability, nasolacrimal duct drainage and poor penetration of cornea.…”

“…TAK1 was found to support vascular formation and endothelial migration. A study showed that pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol provided a potential therapeutic effect on pathological retinal angiogenesis by modulating inflammatory and angiogenic signalling [17,18]. Indeed, constant TAK1 expression protects against endothelial cell apoptosis beyond inflammatory conditions, and genetic TAK1 knockout leads to embryonic lethality due to endothelium death and deleterious vasculature development [19].…”

TAK1 signaling is a potential therapeutic target for pathological angiogenesis

“…Our recent study provided the first piece of evidence that TAK1 inhibition can significantly attenuate retinal neovascularization in a rat model of ischemia-induced retinopathy [83]. The data further suggest that selective inhibition of TAK1 by 5Z-7-oxozeaenol ameliorates the inflammatory response, which contributes to the promotion of aberrant retinal angiogenesis [83]. Furthermore, hypoxia and ischemia in the retina are accompanied by the production of ROS, including H2O2, and the induction of inducible nitric oxide 2 (NOS2).…”

“…TAK1 was found to be activated under hypoxic conditions, which stimulates the expression of proinflammatory and proangiogenic cytokines, including ICAM-1, IL-8 and TNF-a, through NF-κB [52,53,82]. Our recent study provided the first piece of evidence that TAK1 inhibition can significantly attenuate retinal neovascularization in a rat model of ischemia-induced retinopathy [83]. The data further suggest that selective inhibition of TAK1 by 5Z-7-oxozeaenol ameliorates the inflammatory response, which contributes to the promotion of aberrant retinal angiogenesis [83].…”