IKK2 inhibition attenuates laser-induced choroidal neovascularization.
IKK2 inhibition attenuates laser-induced choroidal neovascularization.
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DOI：
10.1371/journal.pone.0087530
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Lu H;Lu Q;Gaddipati S;Kasetti RB;Wang W;Pasparakis M;Kaplan HJ;Li Q
脉络膜新生血管（CNV）是与渗出性年龄相关性黄斑变性（AMD）相关的异常血管生成，AMD是老年人失明的主要原因。炎症被认为是AMD的一个危险因素。IKK2/NF-κB通路通过调节细胞因子、趋化因子、生长因子和血管生成因子的转录，在炎症反应中发挥关键作用。我们使用IKK2条件敲除小鼠或IKK2抑制剂研究了IKK2在激光诱导CNV发展中的功能作用。将IKK2−/flox小鼠与nesting - cre小鼠杂交，产生视网膜神经元组织和IKK2的RPE缺失。在视网膜中Ikk2的缺失没有引起视网膜发育和功能的明显缺陷，但导致激光诱导的CNV显著减少。此外，玻璃体内或球后注射IKK2特异性化学抑制剂TPCA-1也显示出类似的CNV抑制作用。此外，在ARPE-19细胞中，IKK2的体外抑制显著降低了热休克诱导的NFKBIA、IL1B、CCL2、VEGFA、PDGFA、HIF1A和MMP-2的表达，表明IKK2可能调节了激光诱导CNV的多种分子途径。在RPE和脉络膜组织中，激光诱导的VEGFA和HIF1A的体内表达也被TPCA-1处理阻断。因此，在激光诱导的CNV中，IKK2/NF-κB信号通路似乎负责促炎因子和促血管生成因子的产生，这表明这种细胞内通路可能是渗出性AMD异常血管生成的重要治疗靶点。
Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-κB pathway plays a key role in the inflammatory response through regulation of the transcription of cytokines, chemokines, growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2−/flox mice with Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in retinal development or function, but resulted in a significant reduction in laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor, TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in laser-induced CNV. The in vivo laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by TPCA-1 treatment. Thus, IKK2/NF-κB signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
158.5
作者：
Brown, David M.;Kaiser, Peter K.;Schneider, Susan
通讯作者：
Schneider, Susan
影响因子：
158.5
作者：
Gragoudas, ES;Adamis, AP;Guyer, DR
通讯作者：
Guyer, DR
影响因子：
56.9
作者：
Li, QT;Van Antwerp, D;Verma, IM
通讯作者：
Verma, IM
影响因子：
64.8
作者：
KOCH, AE;HALLORAN, MM;POLVERINI, PJ
通讯作者：
POLVERINI, PJ