TAK1 blockade as a therapy for retinal neovascularization

Jiang-Hui Wang; Fan-Li Lin; Jinying Chen; Linxin Zhu; Yu-Fan Chuang; Leilei Tu; Chenkai Ma; Damien Ling; Alex W Hewitt; Ching-Li Tseng; Manisha H Shah; Bang V Bui; Peter van Wijngaarden; Gregory J Dusting; Peng-Yuan Wang; Guei-Sheung Liu

doi:10.1016/j.phrs.2022.106617

TAK1 blockade as a therapy for retinal neovascularization

Pharmacol Res. 2023 Jan:187:106617. doi: 10.1016/j.phrs.2022.106617. Epub 2022 Dec 16.

Authors

Affiliations

¹ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia.
² Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia; Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
³ Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510603, China.
⁴ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
⁵ Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW 1670, Australia.
⁶ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
⁷ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan.
⁸ Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC 3010, Australia.
⁹ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC 3002, Australia.
¹⁰ Oujiang Laboratory, Wenzhou, Zhejiang 325000, China; Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
¹¹ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia; Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC 3002, Australia; Aier Eye Institute, Changsha, Hunan 410015, China. Electronic address: gsliu@unimelb.edu.au.

PMID: 36535572
DOI: 10.1016/j.phrs.2022.106617

Abstract

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.

Keywords: Angiogenesis; Inflammation; Oxygen-induced retinopathy; Retinal neovascularization; TAK1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines / therapeutic use
Disease Models, Animal
Endothelial Cells / metabolism
Humans
Lactones / therapeutic use
Mice
Mice, Inbred C57BL
NF-kappa B
Neovascularization, Pathologic / pathology
Oxygen
Rats
Retinal Diseases* / pathology
Retinal Neovascularization* / metabolism

Substances

7-oxozeanol
Cytokines
Lactones
NF-kappa B
Oxygen
MAP kinase kinase kinase 7