ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis.
ATN-161 as an Integrin α5β1 Antagonist Depresses Ocular Neovascularization by Promoting New Vascular Endothelial Cell Apoptosis.
复制标题
ATN-161 作为整合素 α 5 β 1 拮抗剂通过促进新血管内皮细胞凋亡来抑制眼部新生血管形成
DOI：
10.12659/msm.907446
复制
发表时间：
2018-08-22
期刊：
影响因子：
--
通讯作者：
Xie B
中科院分区：
文献类型：
--
作者：
Sui A;Zhong Y;Demetriades AM;Shen J;Su T;Yao Y;Gao Y;Zhu Y;Shen X;Xie B
ATN-161 (Ac-PHSCN-NH2) 是整合素 α5β1 的拮抗剂，在抑制肿瘤血管生成和其他肿瘤类型的转移方面显示出重要作用。然而，ATN-161的作用机制以及是否能抑制眼部新生血管（NV）尚不清楚。本研究在小鼠模型中研究了 ATN-161 在调节眼部血管生成中的作用，并探讨了潜在的信号通路。采用氧诱导视网膜病变（OIR）小鼠模型和激光诱导脉络膜新生血管（CNV）小鼠模型，通过免疫荧光染色、Western blot分析和平片分析检测整合素α5β1表达以及ATN-161对眼部NV的影响。通过免疫荧光染色、Western blot、实时RT-PCR和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）检测核因子-κB（NF-κB）、基质金属蛋白酶-2/9（MMP-2/9）的激活和细胞凋亡。通过BrdU标记检测细胞增殖情况。在 OIR 和 CNV 小鼠中，与年龄匹配的对照组相比，整合素 α5β1 的蛋白表达水平有所增加。接受 ATN-161 治疗的小鼠视网膜新生血管 (RNV) 和 CNV 显着减少。 ATN-161阻断整合素α5β1可强烈抑制核因子-κB（NF-κB）活化和基质金属蛋白酶-2/9（MMP-2/9）表达并促进细胞凋亡，但ATN-161对CNV小鼠增殖的影响是间接的，需要抑制新生血管形成。通过吡咯烷二硫代氨基甲酸铵 (PDTC) 抑制 NF-κB 活化可减少眼部 NV 中的 RNV 并促进细胞凋亡。 ATN-161 阻断整合素 α5β1 通过抑制 MMP-2/MMP-9 表达并促进眼部 NV 细胞凋亡来减少眼部 NV。
ATN-161 (Ac-PHSCN-NH2), an antagonist of integrin α5β1, has shown an important influence in inhibiting tumor angiogenesis and metastasis of other tumor types. However, the mechanism of action of ATN-161 and whether it can inhibit ocular neovascularization (NV) are unclear. This study investigated the role of ATN-161 in regulating ocular angiogenesis in mouse models and explored the underlying signaling pathway. An oxygen-induced retinopathy (OIR) mouse model and a laser-induced choroidal neovascularization (CNV) mouse model were used to test integrin α5β1 expression and the effect of ATN-161 on ocular NV by immunofluorescence staining, Western blot analysis, and flat-mount analysis. The activation of nuclear factor-κB (NF-κB), matrix metalloproteinase-2/9 (MMP-2/9), and cell apoptosis were detected by immunofluorescence staining, Western blot, real-time RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). The cell proliferation was detected by BrdU labeling. In OIR and CNV mice, the protein expression level of integrin α5β1 increased compared with that in age-matched controls. The mice given ATN-161 had significantly reduced retinal neovascularization (RNV) and CNV. Blocking integrin α5β1 by ATN-161 strongly inhibited nuclear factor-κB (NF-κB) activation and matrix metalloproteinase-2/9 (MMP-2/9) expression and promoted cell apoptosis, but the effect of ATN-161 on proliferation in CNV mice was indirect and required the inhibition of neovascularization. Inhibiting NF-κB activation by ammonium pyrrolidinedithiocarbamate (PDTC) reduced RNV and promoted cell apoptosis in ocular NV. Blocking integrin α5β1 by ATN-161 reduced ocular NV by inhibiting MMP-2/MMP-9 expression and promoting the cell apoptosis of ocular NV.