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

Biochem Pharmacol. 2015 Nov 1;98(1):144-56. doi: 10.1016/j.bcp.2015.09.003. Epub 2015 Sep 5.

Abstract

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.

Keywords: Coenzyme Q(0); Endothelial cells; Heme oxigenase-1; Inflammation; NF-κB; Nrf2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology*
  • Cell Adhesion
  • Cell Line
  • Down-Regulation
  • Gene Expression Regulation
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Molecular Structure
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Benzoquinones
  • I-kappa B Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • ubiquinone-O
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Matrix Metalloproteinase 9