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Oxidized Low-Density Lipoprotein-Induced Matrix Metalloproteinase-9 Expression via PKC-δ/p42/p44 MAPK/Elk-1 Cascade in Brain Astrocytes

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Abstract

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-δ/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.

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Acknowledgements

This work was supported by National Science Council, Taiwan; Grant number: NSC95-2320-B-182-047-MY3, NSC95-2320-B-182-010, and NSC97-2321-B-182-007 (CMY), and NSC96-2320-B-182-009 (HLH) and Chang Gung Medical Research Foundation; Grant number: CMRPD150313, CMRPD140253, and CMRPD150253 (CMY).

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  1. Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Hui-Hsin Wang, Cheng-Ying Wu & Chuen-Mao Yang

  2. Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

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  1. Hui-Hsin Wang
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Wang, HH., Hsieh, HL., Wu, CY. et al. Oxidized Low-Density Lipoprotein-Induced Matrix Metalloproteinase-9 Expression via PKC-δ/p42/p44 MAPK/Elk-1 Cascade in Brain Astrocytes. Neurotox Res 17, 50–65 (2010). https://doi.org/10.1007/s12640-009-9077-2

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