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首页> 外文期刊>Biochemical Pharmacology >Anti-angiogenic properties of coenzyme Q(0) through downregulation of MMP-9/NF-kappa B and upregulation of HO-1 signaling in TNF-alpha-activated human endothelial cells
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Anti-angiogenic properties of coenzyme Q(0) through downregulation of MMP-9/NF-kappa B and upregulation of HO-1 signaling in TNF-alpha-activated human endothelial cells

机译：辅酶Q（0）的抗血管生成特性通过下调MMP-9 /NF-κB和上调TNF-α激活的人内皮细胞中HO-1信号的表达

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Various coenzyme Q(CoQ) analogs have been reported as anti-inflammatory and antioxidant substances. However, coenzyme Q(0) (CoQ(0), 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has not been well studied for its pharmacological efficacies, and its response to cytokine stimulation remains unclear. Therefore, we investigated the potential anti-angiogenic properties of CoQ(0) in human endothelial (EA.hy 926) cells against tumor necrosis factor-alpha (TNF-alpha) stimulation. We found that the non-cytotoxic concentrations of CoQ(0) (2.5-10 mu M) significantly suppressed the TNF-alpha-induced migration/invasion and tube formation abilities of endothelial cells. CoQ(0) suppressed TNF-alpha-induced activity and protein expressions of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) followed by an abridged adhesion of U937 leukocytes to endothelial cells. CoQ(0) treatment remarkably downregulated TNF-alpha-induced nuclear translocation and transcriptional activation of nuclear factor-kappa B (NF-kappa B) possibly through suppressed I-kappa B alpha degradation. Furthermore, CoQ(0) triggered the expressions of heme oxygenase-1 (HO-1) and gamma-glutamylcysteine synthetase (gamma-GCLC), followed by an increased nuclear accumulation of NF-E2 related factor-2 (Nrf2)/antioxidant response element (ARE) activity. In agreement with these, intracellular glutathione levels were significantly increased in CoQ(0) treated cells. More interestingly, knockdown of HO-1 gene by specific shRNA showed diminished anti-angiogenic effects of CoQ(0) against TNF-alpha-induced invasion, tube formation and adhesion of leukocyte to endothelial cells. Our findings reveal that CoQ(0) protective effects against cytokine-stimulation are mediated through the suppression of MMP-9/NF-kappa B and/or activation of HO-1 signaling cascades. This novel finding emphasizes the pharmacological efficacies of CoQ(0) to treat inflammation and angiogenesis. (C) 2015 Elsevier Inc. All rights reserved.
机译：多种辅酶Q（CoQ）类似物已被报道为抗炎和抗氧化物质。但是，辅酶Q（0）（CoQ（0），2,3-二甲氧基-5-甲基-1,4-苯醌），一种新型的醌衍生物，尚未对其药理作用及其对细胞因子的反应进行深入研究。刺激仍不清楚。因此，我们调查了人类内皮细胞（EA.hy 926）对肿瘤坏死因子-α（TNF-alpha）刺激中CoQ（0）的潜在抗血管生成特性。我们发现CoQ（0）（2.5-10μM）的非细胞毒性浓度显着抑制了TNF-α诱导的内皮细胞迁移/侵袭和管形成能力。 CoQ（0）抑制TNF-alpha诱导的活性和基质金属蛋白酶9（MMP-9）和细胞间粘附分子1（ICAM-1）的蛋白质表达，然后抑制U937白细胞与内皮细胞的粘附。 CoQ（0）处理可能通过抑制I-κBα降解显着下调了TNF-α诱导的核易位和核因子-κB（NF-κB）的转录激活。此外，辅酶Q（0）触发血红素加氧酶-1（HO-1）和γ-谷氨酰半胱氨酸合成酶（γ-GCLC）的表达，随后NF-E2相关因子-2（Nrf2）/抗氧化反应的核蓄积增加。元素（ARE）活动。与这些一致，CoQ（0）处理细胞中细胞内谷胱甘肽水平显着增加。更有趣的是，通过特异性shRNA敲低HO-1基因显示出CoQ（0）对TNF-α诱导的侵袭，管形成以及白细胞与内皮细胞粘附的抗血管生成作用减弱。我们的发现表明，通过抑制MMP-9 /NF-κB和/或HO-1信号级联的激活来介导CoQ（0）对细胞因子刺激的保护作用。这一新发现强调了辅酶Q（0）在治疗炎症和血管生成方面的药理作用。 （C）2015 Elsevier Inc.保留所有权利。

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