Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids.
Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids.
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DOI：
10.1016/j.bbalip.2014.12.017
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Al-Shabrawey M
中科院分区：
文献类型：
--
作者：
Ibrahim AS;Tawfik AM;Hussein KA;Elshafey S;Markand S;Rizk N;Duh EJ;Smith SB;Al-Shabrawey M
我们最近证实，12/15-脂氧合酶(LOX)的代谢产物羟基二十碳四烯酸(HETE)通过NADPH氧化酶(NOX)和视网膜血管内皮生长因子(VEGF)和色素上皮衍生因子(PEDF)水平的平衡被破坏，从而导致糖尿病视网膜病变(DR)。在这里，我们测试PEDF是否能改善HETE引起的视网膜血管损伤及其潜在机制。此外，我们还探讨了LOX-NOX系统与DR期间PEDF表达调控之间的因果关系。为此，我们使用了一个实验眼模型，在该模型中，正常小鼠玻璃体内注射12/15HETE加/不加PEDF。然后用荧光素血管造影(FA)评估血管渗漏，然后用光学相干断层扫描(OCT)评估血管生成的存在。FA和OCT分别报告了12-HETE增加的血管渗漏和视网膜前新生血管，这在PEDF治疗组中没有观察到。此外，PEDF显著减轻12-HETE引起的血管细胞和细胞间黏附分子VCAM-1和ICAM-1水平的升高。因此，HETE和PEDF之间的直接关系已经通过使用Müller细胞(RMCs)和人视网膜内皮细胞(HRECs)的体外研究来探索。结果表明，HETES可刺激RMC分泌肿瘤坏死因子-α和IL-6，激活核因子κB，显著增加内皮细胞通透性，降低ZO-1免疫反应性。在PEDF处理的细胞中，所有这些效应都被阻止了。此外，对糖尿病视网膜病变期间PEDF调节的兴趣已经扩展到包括NOX系统。糖尿病小鼠接受NOX抑制剂apocynin治疗或缺乏NOX2治疗后，视网膜PEDF显著恢复至对照水平的80%。总之，我们的发现表明，干扰LOX-NOX信号为通过恢复执行多水平血管保护功能的内源性PEDF而治疗DR开辟了新的方向。
We recently demonstrated that 12/15-lipoxygenase (LOX) derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy (DR) via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor (VEGF) and Pigment Epithelium-Derived Factor (PEDF). Here, we test whether PEDF ameliorates retinal vascular injury induced by HETEs and the underlying mechanisms. Furthermore, we pursue the causal relationship between LOX-NOX system and regulation of PEDF expression during DR. For these purposes, we used an experimental eye model in which normal mice were injected intravitreally with 12/15HETE with/without PEDF. Thereafter, Fluorescein Angiography (FA) was used to evaluate the vascular leakage, followed by Optical coherence tomography (OCT) to assess the presence of angiogenesis. FA and OCT reported an increased vascular leakage and pre-retinal neovascularization, respectively, in response to 12-HETE that were not observed in PEDF-treated group. Moreover, PEDF significantly attenuated the increased levels of vascular cell and intercellular adhesion molecules, VCAM-1 and ICAM-1, elicited by 12-HETE injection. Accordingly, the direct relationship between HETE and PEDF has been explored through in-vitro studies using Müller cells (rMCs) and human retinal endothelial cells (HRECs). The results showed that HETEs triggered the secretion of TNF-α and IL-6, as well as activation of NFκB in rMCs and significantly increased permeability and reduced zonula occludens protein-1 (ZO-1) immunoreactivity in HRECs. All these effects were prevented in PEDF-treated cells. Furthermore, interest in PEDF regulation during DR has been expanded to include NOX system. Retinal PEDF was significantly restored in diabetic mice treated with NOX inhibitor, apocynin, or lacking NOX2 up to 80% of the control level. Collectively, our findings suggest that interfering with LOX-NOX signaling opens up a new direction for treating DR by restoring endogenous PEDF that carries out multilevel vascular protective functions.
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影响因子：
4.2
作者：
He SS;Shi HS;Yin T;Li YX;Luo ST;Wu QJ;Lu L;Wei YQ;Yang L
通讯作者：
Yang L
影响因子：
4.2
作者：
Duh, EJ;Yang, HS;Zack, DJ
通讯作者：
Zack, DJ
DOI：
10.1073/pnas.0308342101
发表时间：
2004-04-27
影响因子：
11.1
作者：
Liu, H;Ren, JG;Tong, PY
通讯作者：
Tong, PY
影响因子：
--
作者：
Kim, Ji Min;Lee, Eun Kyeong;Chung, Hae Young
通讯作者：
Chung, Hae Young
影响因子：
2.1
作者：
Koskela, U. E.;Kuusisto, S. M.;Liinamaa, M. J.
通讯作者：
Liinamaa, M. J.