miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7
miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7
复制标题
miR-539-5p 通过靶向 CXCR7 抑制实验性脉络膜新生血管形成。
DOI：
10.1096/fj.201700640r
复制
发表时间：
2018-03-01
期刊：
影响因子：
4.8
通讯作者：
Yuan, Fei
中科院分区：
文献类型：
--
作者：
Feng, Yifan;Wang, Jing;Yuan, Fei
基质细胞衍生因子-1（SDF-1）先前已被证实通过其受体CXC趋化因子受体（CXCR）4参与脉络膜新生血管（CNV）的形成; CXCR 7是最近鉴定的SDF-1受体。CXCR 7在CNV中的分子机制和治疗价值尚不清楚。在这项研究中，实验性CNV诱导的激光光凝在Brown-Norway色素大鼠，异常CXCR 7过表达检测到视网膜色素上皮/脉络膜/巩膜组织的激光损伤的眼睛。通过CXCR 7敲低或中和抗体给药阻断CXCR 7活化可抑制SDF-1诱导的细胞存活和体外人视网膜微血管内皮细胞（HRMEC）的小管形成，并减少体内CNV渗漏和病变大小。通过使用microRNA阵列筛选和生物信息学分析，我们鉴定出miR-539- 5 p是CXCR 7的调节因子。用miR-539- 5 p模拟物转染HRMEC和脉络膜-视网膜内皮（RF/6A）细胞抑制其存活和管形成，而CXCR 7过表达挽救了miR-539- 5 p的抑制作用。另外，通过玻璃体内注射在体内证明了miR-539- 5 p模拟物的抗血管生成活性。CXCR 7下游的ERK 1/2和AKT信号转导参与miR-539- 5 p对内皮细胞行为的调节。这些发现表明，miR-539- 5 p/CXCR 7水平的操纵可能在CNV相关疾病中具有重要的治疗意义。
Stromal cell-derived factor-1 (SDF-1) has been previously confirmed to participate in the formation of choroidal neovascularization (CNV) via its receptor, CXC chemokine receptor (CXCR) 4; CXCR7 is a recently identified receptor for SDF-1. The molecular mechanisms and therapeutic value of CXCR7 in CNV remain undefined. In this study, experimental CNV was induced by laser photocoagulation in Brown-Norway pigmented rats, and aberrant CXCR7 overexpression was detected in the retinal pigment epithelial/choroid/sclera tissues of laser-injured eyes. Blockade of CXCR7 activation via CXCR7 knockdown or neutralizing Ab administration inhibited SDF-1-induced cell survival and the tubular formation of human retinal microvascular endothelial cells (HRMECs) in vitro and reduced CNV leakage and lesion size in vivo. By using microRNA array screening and bioinformatic analyses, we identified miR-539-5p as a regulator of CXCR7. Transfection of HRMECs and choroid-retinal endothelial (RF/6A) cells with the miR-539-5p mimic inhibited their survival and tube formation, whereas CXCR7 overexpression rescued the suppressive effect of miR-539-5p. The antiangiogenic activities of the miR-539-5p mimic were additionally demonstrated in vivo by intravitreal injection. ERK1/2 and AKT signaling downstream of CXCR7 is involved in the miR-539-5p regulation of endothelial cell behaviors. These findings suggest that the manipulation of miR-539-5p/CXCR7 levels may have important therapeutic implications in CNV-associated diseases.