Oxidized low-density lipoprotein-induced matrix metalloproteinase-9 expression via PKC-delta/p42/p44 MAPK/Elk-1 cascade in brain astrocytes.
After ischemic injury to brain, disruption of the blood-brain barrier (BBB) raises the possibility of exposing the central nervous system (CNS) to oxidized low-density lipoprotein (oxLDL), a risk factor implicated in neurodegenerative diseases. Matrix metalloproteinases (MMPs), especially MMP-9, contribute to extracellular matrix (ECM) remodeling during the CNS diseases. However, the molecular mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes remained unclear. Here, we reported that oxLDL induced MMP-9 expression via a PKC-delta/p42/p44 MAPK-dependent Elk-1 activation in rat brain astrocyte (RBA)-1 cells, revealed by gelatin zymography, RT-PCR, and Western blotting analyses. These responses were attenuated by pretreatment with pharmacological inhibitors and transfection with dominant negative mutants. Moreover, Elk-1-mediated MMP-9 gene transcription was confirmed by transfection with an Elk-1 binding site-mutated MMP-9 promoter construct (mt-Ets-MMP9), which blocked oxLDL-stimulated MMP-9 luciferase activity. Understanding the regulatory mechanisms by which oxLDL induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain diseases.
Wang
Hui-Hsin
HH
Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan.
Hsieh
Hsi-Lung
HL
Wu
Cheng-Ying
CY
Yang
Chuen-Mao
CM
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D001921:Brain / Q000166:cytology*; D002465:Cell Movement / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D051745:Protein Kinase C-delta / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D050807:ets-Domain Protein Elk-1; D051745:Protein Kinase C-delta; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9