title: Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells.
abstract: Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-β1 (TGF-β1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-β1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-β1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-β1-induced expression of PAI-1 without the inhibition of TβRII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Ji-Hak
authors.initials: JH
authors.lastname: Jeong
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Jeong
authors.forename: Kwan-Kyu
authors.initials: KK
authors.lastname: Park
authors.forename: Yoon-Yub
authors.initials: YY
authors.lastname: Park
authors.forename: Yong-Suk
authors.initials: YS
authors.lastname: Moon
authors.forename: Hong-Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Il-Kyung
authors.initials: IK
authors.lastname: Chung
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Hyeun-Wook
authors.initials: HW
authors.lastname: Chang
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000475:Alkenes; D061965:Matrix Metalloproteinase Inhibitors; D010636:Phenols; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; C415745:ascochlorin