Prodrug of epigallocatechin-3-gallate alleviates choroidal neovascularization via down-regulating HIF-1α/VEGF/VEGFR2 pathway and M1 type macrophage/microglia polarization - 30/11/19

Doi : 10.1016/j.biopha.2019.109606

Jiaowen Xu ^a,^{^{1
These authors contributed equally to this work.}}, Yuanyuan Tu ^b,^{^{1
These authors contributed equally to this work.}}, Ying Wang ^b,^c, Xun Xu ^d,^e, Xiaodong Sun ^d,^e, Laiqing Xie ^a, Qingliang Zhao ^b, Yang Guo ^a, Yonghui Gu ^c, Jingxia Du ^a, Shu Du ^b, Manhui Zhu ^b,⁎, ^{^{1
These authors contributed equally to this work.}} , E. Song ^b,⁎, ^{^{1
These authors contributed equally to this work.}}
^a Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
^b Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
^c Department of Ophthalmology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
^d Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai, China
^e Department of Ophthalmology, Shanghai First People’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China

^⁎Corresponding authors at: Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China.Lixiang Eye Hospital of Soochow UniversitySuzhouJiangsuChina

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Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly and is attributed to choroidal neovascularization (CNV), which is a feature of wet AMD. The hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to the pathogenesis of CNV. M1-type macrophages/microglia secrete interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), facilitating the development of CNV. Epigallocatechin-3-gallate (EGCG) is a kind of polyphenol in green tea that exerts anti-inflammatory and antiangiogenic effects. In this study, a prodrug of EGCG (pro-EGCG) alleviated mouse laser-induced CNV leakage and reduced CNV area by down-regulating HIF-1α/VEGF/VEGFR2 pathway; M1-type macrophage/microglia polarization; as well as endothelial cell viability, proliferation, migration and tube formation, indicating a novel potential therapy for AMD.

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Keywords : Prodrug of epigallocatechin-3-gallate (pro-EGCG), Age-related macular degeneration (AMD), Choroidal neovascularization (CNV), HIF-1α/VEGF/VEGFR2 pathway, M1-type macrophages/microglia

Plan

Introduction

Materials and methods

Mouse laser-induced CNV model

Western blot

Immunohistochemistry of choroidal flat-mounts

ELISA

Immunohistochemistry stain

Synthesis of pro-EGCG

Pro-EGCG mouse oral gavage

Fundus fluorescein angiography (FFA)

Indocyanine green (ICG) angiography

Quantitative real-time PCR (qRT-PCR)

B-End3 cell culture and treatment

Cell counting Kit-8 (CCK‑8) assay

5-Ethynyl-2′-deoxyuridine (EdU) assay

Transwell migration assay

Tube formation assay

Statistical analysis

Results

The levels of HIF-1α/VEGF/VEGFR2 pathway proteins and M1-type macrophages/microglia are increased in mouse CNV regions

Pro-EGCG alleviates CNV formation

Pro-EGCG inhibits CNV-induced HIF-1α/VEGF/VEGFR2 pathway

Pro-EGCG downregulates CNV-induced M1-type macrophage/microglia polarization

Pro-EGCG reduces the viability, proliferation, migration and tube formation of b-End3 cells

Discussion

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Vol 121

Article 109606- janvier 2020 Retour au numéro

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Prodrug of epigallocatechin-3-gallate alleviates choroidal neovascularization via down-regulating HIF-1α/VEGF/VEGFR2 pathway and M1 type macrophage/microglia polarization - 30/11/19

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