科研之友
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摘要
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.
