Inhibitory role of magnolol on proliferative capacity and matrix metalloproteinase-9 expression in TNF-alpha-induced vascular smooth muscle cells.
Magnolol, an active component extracted from Magnolia officinalis, has been reported to inhibit the development of atherosclerotic disease. However, it is not known whether magnolol exerts similar cardioprotective effects in cells treated with TNF-alpha. In the present study, magnolol treatment was found to show potent inhibitory effects on cell proliferation in cultured VSMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK) 1/2 activity and G1 cell cycle arrest. Magnolol treatment strongly induced the expression of p21WAF1, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G1 progression. In addition to G1 cell cycle arrest and growth inhibition in VSMC, magnolol also caused the strong inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in a dose-dependent manner as determined by zymography and immunoblot. Moreover, magnolol treatment strongly decreased MMP-9 promoter activity in response to TNF-alpha. We further demonstrated that magnolol reduced the transcriptional activity of NF-kappaB and activation protein-1 (AP-1), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results show that magnolol inhibits cell proliferation, G1 to S phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC. The findings of the present study reveal a potential mechanism that explains the anti-atherogenic activity of magnolol.
Kim
Hong-Man
HM
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Bae
Sung-Jin
SJ
Kim
Dong-Wook
DW
Kim
Bo-Kyung
BK
Lee
Soo-Bok
SB
Lee
Ung-Soo
US
Kim
Cheorl-Ho
CH
Moon
Sung-Kwon
SK
D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D001713:Biphenyl Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017705:Lignans; D016328:NF-kappa B; D010936:Plant Extracts; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C005498:magnolol; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9