Anti-angiogenic properties of coenzyme Q₀ through downregulation of MMP-9/NF-魏B and upregulation of HO-1 signaling in TNF-伪-activated human endothelial cells

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• 作者：Hsin-Ling Yang^a ; Mallikarjuna Korivi^a ; ^b ; ¹ ; Ming-Wei Lin^a ; ¹ ; Ssu-Ching Chen^c ; Chih-Wei Chou^b ; You-Cheng Hseu^b ; ^d ; ^{ychseu@mail.cmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Coenzyme Q0 ; Endothelial cells ; Inflammation ; Heme oxigenase-1 ; NF-魏B ; Nrf2
• 刊名：Biochemical Pharmacology
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：98
• 期：1
• 页码：144-156
• 全文大小：2654 K

文摘

Various coenzyme Q (CoQ) analogs have been reported as anti-inflammatory and antioxidant substances. However, coenzyme Q₀ (CoQ₀, 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 CoQ₀ in human endothelial (EA.hy 926) cells against tumor necrosis factor-伪 (TNF-伪) stimulation. We found that the non-cytotoxic concentrations of CoQ₀ (2.5–10 渭M) significantly suppressed the TNF-伪-induced migration/invasion and tube formation abilities of endothelial cells. CoQ₀ suppressed TNF-伪-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. CoQ₀ treatment remarkably downregulated TNF-伪-induced nuclear translocation and transcriptional activation of nuclear factor-魏B (NF-魏B) possibly through suppressed I-魏B伪 degradation. Furthermore, CoQ₀ triggered the expressions of heme oxygenase-1 (HO-1) and 纬-glutamylcysteine synthetase (纬-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 CoQ₀ treated cells. More interestingly, knockdown of HO-1 gene by specific shRNA showed diminished anti-angiogenic effects of CoQ₀ against TNF-伪-induced invasion, tube formation and adhesion of leukocyte to endothelial cells. Our findings reveal that CoQ₀ protective effects against cytokine-stimulation are mediated through the suppression of MMP-9/NF-魏B and/or activation of HO-1 signaling cascades. This novel finding emphasizes the pharmacological efficacies of CoQ₀ to treat inflammation and angiogenesis.