Journal Article

Inhibition of Hypoxia-Induced Retinal Angiogenesis by Specnuezhenide, an Effective Constituent of Ligustrum lucidum Ait., through Suppression of the HIF-1α/VEGF Signaling Pathway

Ke, Xiao, Zhang, Zhirong, Gao, Xiaoping, Zhang, Hongcheng, Wang, Wei, Hao, Xiaofeng, Ma, Na, Wu, Jianming, Zhao, Manxi, Fu, Wei

2016

Overview

Specnuezhenide (SPN), one of the main ingredients of Chinese medicine “Nü-zhen-zi”, has anti-angiogenic and vision improvement effects. However, studies of its effect on retinal neovascularization are limited so far. In the present study, we established a vascular endothelial growth factor A (VEGFA) secretion model of human acute retinal pigment epithelial-19 (ARPE-19) cells by exposure of 150 μM CoCl2 to the cells and determined the VEGFA concentrations, the mRNA expressions of VEGFA, hypoxia inducible factor-1α (HIF-1α) & prolyl hydroxylases 2 (PHD-2), and the protein expressions of HIF-1α and PHD-2 after treatment of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1, 1.0 μg/mL) or SPN (0.2, 1.0 and 5.0 μg/mL). Furthermore, rat pups with retinopathy were treated with SPN (5.0 and 10.0 mg/kg) in an 80% oxygen atmosphere and the retinal avascular areas were assessed through visualization using infusion of ADPase and H&E stains. The results showed that SPN inhibited VEGFA secretion by ARPE-19 cells under hypoxia condition, down-regulated the mRNA expressions of VEGFA and PHD-2 slightly, and the protein expressions of VEGFA, HIF-1α and PHD-2 significantly in vitro. SPN also prevented hypoxia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy in vivo. These results indicate that SPN ameliorates retinal neovascularization through inhibition of HIF-1α/VEGF signaling pathway. Therefore, SPN has the potential to be developed as an agent for the prevention and treatment of diabetic retinopathy.

• Publisher: MDPI,MDPI AG
• Subject: angiogenesis / Angiogenesis Inhibitors - isolation & purification / Angiogenesis Inhibitors - pharmacology / Animals / Cell Hypoxia / Cell Line / Cobalt - pharmacology / Diabetic Retinopathy - drug therapy / Diabetic Retinopathy - genetics / Diabetic Retinopathy - metabolism / Diabetic Retinopathy - pathology / Disease Models, Animal / Epithelial Cells - cytology / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Gene Expression Regulation / Glucosides - isolation & purification / Glucosides - pharmacology / Humans / Hypoxia - complications / Hypoxia - drug therapy / Hypoxia - genetics / Hypoxia - pathology / Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / hypoxia-inducible factor-1 / Hypoxia-Inducible Factor-Proline Dioxygenases - genetics / Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism / Indazoles - pharmacology / Ligustrum - chemistry / Ligustrum lucidum / oxygen-induced retinopathy / Plant Extracts - chemistry / Pyrans - isolation & purification / Pyrans - pharmacology / Rats / Rats, Sprague-Dawley / Retinal Neovascularization - drug therapy / Retinal Neovascularization - etiology / Retinal Neovascularization - genetics / Retinal Neovascularization - pathology / Retinal Pigment Epithelium - cytology / Retinal Pigment Epithelium - drug effects / Retinal Pigment Epithelium - metabolism / Signal Transduction / specnuezhenide / vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism