Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 199, Issue 2, Pages 112-119Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2012.06.003
Keywords
Pimaric acid; Aralia cordata; Matrix metalloproteinase-9; Human aortic smooth muscle cells; Migration; TNF-alpha
Funding
- Ministry of Food, Agriculture, Forestry, and Fisheries (MIFAFF) [20100222]
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Many studies have indicated that activation of matrix metalloproteinase (MMP)-9 and smooth muscle cell (SMC) migration are involved in neointimal formation and atherosclerosis. In this study, we revealed that pimaric acid (PiMA) purified from Aralia cordata had an inhibitory effect on MMP-9 production and migration of human aortic smooth muscle cells (HASMCs) induced by tumor necrosis factor (TNF)-alpha. Down-regulated MMP-9 mRNA transcription was detected in PiMA-treated cells using RT-PCR and the luciferase-tagged MMP-9 promoter assay. Results of an electrophoretic mobility shift assay indicated that PiMA-treated HASMCs showed decreased binding activity of nuclear factor (NF)-kappa B and activator protein-1 transcription factors. A Western-blot analysis using nuclear extract demonstrated that PiMA reduced the levels of NF-kappa B p65, c-Fos, p-c-Jun. Jun-D, and p-ATF2 proteins in the nucleus. In addition, TNF-alpha stimulated mitogen activated protein kinase (MAPK) containing extracellular signal regulated kinase 1 and 2, p38, and c-Jun N-terminal kinase was inhibited by PiMA. Using the Transwell system, we found that PiMA inhibited TNF-alpha stimulated HASMC migration/invasion in a dose-dependent manner. To confirm whether MAPK mediated MMP-9 expression, we used MAPK inhibitors including U0126, SB253580, and SP600125 and found that those inhibitors reduced MMP-9 expression and HASMC migration/invasion. These results suggest that PiMA has potent anti-atherosclerotic activity with inhibitory action on MMP-9 production and cell migration in TNF-alpha-induced HASMCs. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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