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Ochnaflavone inhibits TNF-alpha-induced human VSMC proliferation via regulation of cell cycle, ERK1/2, and MMP-9.

Abstract
Ochnaflavone (c-3 of apigenin-0-c-4 of apigenin; OC), a biflavonoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. OC is known to have anti-fungal and anti-inflammatory activities. However, it is not known whether OC exerts similar cardioprotective effects in cells treated with tumor necrosis factor (TNF)-alpha. In this study, we isolated OC from Lonicera japonica and studied its effect on matrix metalloproteinase-9 (MMP-9) gene expression in human aortic smooth muscle cells (HASMC). Furthermore, we investigated whether OC exerts the multiple suppressive effects on cytokine TNF-alpha-induced HASMC. Treatment of OC showed its potent inhibitory effects on DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and G1 cell cycle arrest. Treatment of OC, which induced a cell cycle block in G1-phase, induced downregulation of cyclins and CDKs and upregulation of the CDK inhibitor p21(waf1) expression, whereas upregulation of p27 or p53 by OC was not observed. Because anti-atherogenic effects need not be limited to anti-proliferation, we decided to examine whether OC exerts inhibitory effects on MMP-9 activity in TNF-alpha-induced HASMC. OC inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by downregulation of MMP-9, which was transcriptionally regulated at nuclear factor (NF)-kappaB site and activation protein (AP)-1 site in the MMP-9 promoter. These findings indicate the efficacy of OC in inhibiting cell proliferation, G1 to S-phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC. The findings of the present study may provide a potential mechanism that explains the anti-atherogenic activity of OC.
AuthorsSeok-Jong Suh, Un-Ho Jin, Sung-Hoon Kim, Hyeun-Wook Chang, Jong-Keun Son, Seung Ho Lee, Kun-Ho Son, Cheorl-Ho Kim
JournalJournal of cellular biochemistry (J Cell Biochem) Vol. 99 Issue 5 Pg. 1298-307 (Dec 01 2006) ISSN: 0730-2312 [Print] United States
PMID16795041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2006 Wiley-Liss, Inc.
Chemical References
  • Cyclin-Dependent Kinase Inhibitor p21
  • Flavonoids
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • ochnaflavone
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Matrix Metalloproteinase 9
Topics
  • Cell Cycle (physiology)
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
  • Enzyme Induction
  • Flavonoids (chemistry, pharmacology)
  • Humans
  • Matrix Metalloproteinase 9 (genetics, metabolism)
  • Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
  • Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
  • Molecular Structure
  • Muscle, Smooth, Vascular (cytology)
  • Myocytes, Smooth Muscle (cytology, physiology)
  • NF-kappa B (genetics, metabolism)
  • Promoter Regions, Genetic
  • Tumor Necrosis Factor-alpha (metabolism)

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