Anti-angiogenic properties of coenzyme Q0 through downregulation of MMP-9/NF-κB and upregulation of HO-1 signaling in TNF-α-activated human endothelial cells.
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-α (TNF-α) stimulation. We found that the non-cytotoxic concentrations of CoQ0 (2.5-10μM) significantly suppressed the TNF-α-induced migration/invasion and tube formation abilities of endothelial cells. CoQ0 suppressed TNF-α-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-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) possibly through suppressed I-κBα degradation. Furthermore, CoQ0 triggered the expressions of heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-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-α-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-κB and/or activation of HO-1 signaling cascades. This novel finding emphasizes the pharmacological efficacies of CoQ0 to treat inflammation and angiogenesis.
Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
Hsin-Ling
HL
Yang
Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan; Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
Mallikarjuna
M
Korivi
Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
Ming-Wei
MW
Lin
Department of Life Sciences, National Central University, Chung-Li 32001, Taiwan.
Ssu-Ching
SC
Chen
Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan.
Chih-Wei
CW
Chou
Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: ychseu@mail.cmu.edu.tw.
You-Cheng
YC
Hseu
D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D016227:Benzoquinones; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C109863:ubiquinone-O; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9
Coenzyme Q(0); Endothelial cells; Heme oxigenase-1; Inflammation; NF-κB; Nrf2