Ascochlorin suppresses oxLDL-induced MMP-9 expression by inhibiting the MEK/ERK signaling pathway in human THP-1 macrophages.
The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial walls of arteries and the transformation of monocytes from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). Also, during a chronic inflammatory response, monocytes/macrophages produce the 92-kDa matrix metalloproteinase-9 (MMP-9) that may contribute to the extravasation, migration, and tissue remolding capacities of the phagocytic cells. Here, we investigate the effect of ascochlorin (ASC), a prenylphenol antiviral compound from the fungus Ascochyta viciae, on oxLDL-induced MMP-9 expression and activity in human THP-1 macrophages. ASC reduced oxLDL-induced MMP-9 expression and activity in a time-dependent and dose-dependent manner. Also, an analysis of MMP-9 activity using pharmacologic inhibitors showed that ASC inhibits MMP-9 activity via the extracellular signal-regulated kinase 1 and kinase 2 pathways. Our results suggest that ASC may be useful as a potent clinical antiatherogenic agent, a topic of considerable interest in the biological chemistry of chemotherapeutic agents.
Kang
Jeong Han
JH
Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Korea.
Kim
June-Ki
JK
Park
Won-Hwan
WH
Park
Kwan-Kyu
KK
Lee
Tae-Sung
TS
Magae
Junji
J
Nakajima
Hiroo
H
Kim
Cheorl-Ho
CH
Chang
Young-Chae
YC
D000475:Alkenes / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D015398:Signal Transduction
D000475:Alkenes; D002070:Butadienes; D005419:Flavonoids; D008077:Lipoproteins, LDL; D009570:Nitriles; D010636:Phenols; C113580:U 0126; C099252:oxidized low density lipoprotein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; C415745:ascochlorin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one