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TAK1 blockade as a therapy for retinal neovascularization


Wang, JH and Lin, F-L and Chen, J and Zhu, L and Chuang, Y-F and Tu, L and Ma, C and Ling, D and Hewitt, AW and Tseng, CL and Shah, MH and Bui, BV and van Wijngaarden, P and Dusting, GJ and Wang, PY and Hewitt, A, TAK1 blockade as a therapy for retinal neovascularization, Pharmacological Research, 187 Article 106617. ISSN 1043-6618 (2023) [Refereed Article]

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DOI: doi:10.1016/j.phrs.2022.106617


Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

Item Details

Item Type:Refereed Article
Keywords:Angiogenesis; Inflammation; Oxygen-induced retinopathy; Retinal neovascularization; TAK1.
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Optical technology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Lin, F-L (Dr Fan-Li Lin)
UTAS Author:Zhu, L (Ms Linxin Zhu)
UTAS Author:Chuang, Y-F (Dr Yu-Fan Chuang)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:155575
Year Published:2023
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-03-01
Last Modified:2023-03-01

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