A Novel Small Peptide H-KI20 Inhibits Retinal Neovascularization Through the JNK/ATF2 Signaling Pathway.
A Novel Small Peptide H-KI20 Inhibits Retinal Neovascularization Through the JNK/ATF2 Signaling Pathway.
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DOI：
10.1167/iovs.62.1.16
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发表时间：
2021-01-04
影响因子：
4.4
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Wang R;Xu Y;Niu C;Gao X;Xu X
大量证据表明，抗血管内皮生长因子（抗VEGF）治疗新生血管性眼病的益处。然而，频繁注射的高成本、副作用和不便需要替代的新型候选药物。本研究旨在分析肽H-KI 20的抗血管生成作用并阐明其信号转导机制。在人视网膜微血管内皮细胞（HREC）中进行活细胞培养和示踪、伤口愈合测定和管形成。采用鸡胚绒毛尿囊膜和小鼠氧诱导缺血性视网膜病变模型观察H-KI 20的体内作用。检测细胞内信号通路。采用分子对接和表面等离子体共振技术验证H-KI 20与c-Jun N-末端激酶2（JNK 2）的直接相互作用。H-KI 20在体外和体内均具有良好的渗透能力。它抑制运动，迁移，和管形成的HREC，没有细胞毒性，并抑制血管生成在体内。此外，H-KI 20处理通过下调p-JNK降低VEGF刺激的活化转录因子2（ATF 2）的磷酸化水平。H-KI 20直接与JNK 2结合，解离常数值为83.68 µM。ATF 2的敲低减弱了VEGF诱导的HREC管形成，并降低了HREC的运动速度。H-KI 20在体外和体内均抑制血管生成。H-KI 20可降低VEGF刺激的p-ATF 2/ATF 2和p-JNK/JNK比值，H-KI 20可直接靶向JNK 2。此外，ATF 2在VEGF诱导的视网膜新生血管中的关键作用首次得到阐明。综上所述，H-KI 20作为一种持续的低毒性肽显示出病理性视网膜血管生成的潜力。
Abundant evidence has shown benefits of antivascular endothelial growth factor (anti-VEGF) therapies in neovascular eye diseases. However, the high cost, side effects, and inconvenience of frequent injections demand alternative novel drug candidates. This study aimed to analyze antiangiogenic effects of peptide H-KI20 and illustrated signaling mechanisms. Live cell culture and tracing, wound healing assay, and tube formation were performed in human retinal microvascular endothelial cells (HRECs). The chick embryo chorioallantoic membrane and mouse oxygen-induced ischemic retinopathy model were applied to examine the effects of H-KI20 in vivo. The intracellular signaling pathways were examined. Molecular docking and surface plasmon resonance assay were used to validate the direct interaction of H-KI20 and c-Jun N-terminal kinase 2 (JNK2). H-KI20 had high penetration ability in vitro and in vivo. It inhibited motility, migration, and tube formation of HRECs, without cytotoxicity, and inhibited angiogenesis in vivo. Furthermore, H-KI20 treatment reduced the phosphorylation level of activating transcription factor 2 (ATF2) stimulated by VEGF via downregulating p-JNK. H-KI20 bound to JNK2 directly with a dissociation constant value of 83.68 µM. The knockdown of ATF2 attenuated VEGF-induced tube formation and decreased the movement speed of HRECs. H-KI20 inhibited angiogenesis both in vitro and in vivo. The ratios of p-ATF2/ATF2 and p-JNK/JNK stimulated by VEGF were decreased by H-KI20, and H-KI20 targeted JNK2 directly. In addition, the pivotal role of ATF2 in VEGF-induced retinal neovascularization was elucidated for the first time. Taken together, H-KI20 displays potential for pathological retinal angiogenesis as a sustained and low-toxic peptide.
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影响因子：
12.8
作者：
Gonsalves, Caryn S.;Crable, Scott;Chandra, Sharat;Li, Wei;Kalra, Vijay K.;Joiner, Clinton H.
通讯作者：
Joiner, Clinton H.
影响因子：
20.1
作者：
Cuhlmann, Simon;Van der Heiden, Kim;Evans, Paul C.
通讯作者：
Evans, Paul C.
影响因子：
14
作者：
Chen, Chong;Liu, Kun;Xu, X.
通讯作者：
Xu, X.
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
168.9
作者：
Hellstrom, Ann;Smith, Lois E. H.;Dammann, Olaf
通讯作者：
Dammann, Olaf