Deoxypodophyllotoxin, flavolignan, from Anthriscus sylvestris Hoffm. inhibits migration and MMP-9 via MAPK pathways in TNF-alpha-induced HASMC.
The matrix metalloproteinases (MMP-9 and MMP-2) in aortic smooth muscle cells (SMC) play key roles in the pathogenesis atherosclerosis. The SMC migration into the vascular wall via the bloodstream is directly linked with MMP-9 expression. Deoxypodophyllotoxin (DPT), a naturally occurring flavolignan with anti-inflammatory activity, was isolated from Anthriscus sylvestris Hoffm. and has been known inhibit the expression of MMP-9 in tumor necrosis factor-alpha (TNF-alpha) stimulated human aortic smooth muscle cells (HASMC). In this study, DPT was purified and demonstrated to inhibit the MMP-9/2 activities in TNF-alpha-induced HASMC. In addition, MMP-9 expression and migration was strongly inhibited by DPT in TNF-alpha-induced HASMC. To examine whether TNF-alpha-induced MMP-9 expressions are involved with migrations of HASMC, reverse transcription-polymerase chain reaction (RT-PCR) and luciferase-tagged promoter analysis were applied. These experiments revealed that DPT inhibited the mRNA transcription of MMP-9 gene expression. Furthermore, Western blot analysis indicated that the TNF-alpha-induced phosphorylation of extracellular signal regulated kinase 1 and 2 (ERK1/2), p38 and c-Jun N-terminal kinase (JNK) were strongly inhibited by DPT. From these results, it is concluded that DPT has an inhibitory activities on migration and MMP-2/9 activities, and MMP-9 transcription in HASMC.
Suh
Seok-Jong
SJ
Department of Biological Science, Sungkyunkwan University, Chunchun-Dong 300, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, Republic of Korea.
Kim
Jeong-Ran
JR
Jin
Un-Ho
UH
Choi
Hong-Seo
HS
Chang
Young-Chae
YC
Lee
Young-Choon
YC
Kim
Sung-Hoon
SH
Lee
In-Seon
IS
Moon
Tae Chul
TC
Chang
Hyeun-Wook
HW
Kim
Cheorl-Ho
CH
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019661:Apiaceae / Q000737:chemistry / Q000502:physiology*; D002464:Cell Migration Inhibition / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D018517:Plant Roots; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D004365:Drugs, Chinese Herbal; D017705:Lignans; D061965:Matrix Metalloproteinase Inhibitors; D010936:Plant Extracts; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; C014451:deoxypodophyllotoxin; D020780:Matrix Metalloproteinase 9; D011034:Podophyllotoxin