Document Detail


Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and JNK-dependent AP-1 pathway in brain astrocytes.
MedLine Citation:
PMID:  18661553     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Upregulation of matrix metalloproteinases (MMPs), especially MMP-9, by oxidized low-density lipoprotein (oxLDL) is implicated in many inflammatory diseases including brain injury. However, the signaling mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes largely remain unknown. Here we report that oxLDL induces expression of proMMP-9 via a MAPK-dependent AP-1 activation in rat brain astrocyte (RBA)-1 cells. Results revealed by gelatin zymography, RT-PCR, and Western blotting analyses showed that oxLDL-induced proMMP-9 gene expression was mediated through Akt, JNK1/2, and p42/p44 MAPK phosphorylation in RBA-1 cells. These responses were attenuated by inhibitors of PI3K (LY294002), JNK (SP600125), and p42/p44 MAPK (PD98059), or transfection with dominant negative mutants and short hairpin RNA. Moreover, we demonstrated that AP-1 (i.e., c-Fos/c-Jun) is crucial for oxLDL-induced proMMP-9 expression which was attenuated by pretreatment with AP-1 inhibitor (curcumin). The regulation of MMP-9 gene transcription by AP-1 was confirmed by oxLDL-stimulated MMP-9 luciferase activity which was totally lost in cells transfected with the AP-1 binding site-mutated MMP-9 promoter construct (mt-AP1-MMP-9). These results suggested that oxLDL-induced proMMP-9 expression is mediated through PI3K/Akt, JNK1/2, and p42/p44 MAPK leading to AP-1 activation. Understanding the regulatory mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain injuries and diseases.
Authors:
Hui-Hsin Wang; Hsi-Lung Hsieh; Cheng-Ying Wu; Chi-Chin Sun; Chuen-Mao Yang
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Glia     Volume:  57     ISSN:  1098-1136     ISO Abbreviation:  Glia     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-11-18     Completed Date:  2009-05-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8806785     Medline TA:  Glia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24-38     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Astrocytes / enzymology*,  metabolism,  physiology
Brain / enzymology*,  metabolism,  physiology
Cell Line
Enzyme Activation / genetics
Enzyme Precursors / biosynthesis*,  genetics
Gene Expression Regulation, Enzymologic / genetics
Humans
Lipoproteins, LDL / physiology*
MAP Kinase Kinase 4 / physiology*
MAP Kinase Signaling System / genetics
Matrix Metalloproteinase 9 / biosynthesis*,  genetics
Mitogen-Activated Protein Kinase 1 / physiology*
Mitogen-Activated Protein Kinase 3 / physiology*
Oxidation-Reduction
Rats
Transcription Factor AP-1 / metabolism*
Chemical
Reg. No./Substance:
0/Enzyme Precursors; 0/Lipoproteins, LDL; 0/Transcription Factor AP-1; 0/oxidized low density lipoprotein; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.12.2/MAP Kinase Kinase 4; EC 3.4.24.-/pro-matrix metalloproteinase 9; EC 3.4.24.35/Matrix Metalloproteinase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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