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    RNA-binding proteins mediate anti-inflammatory regulation of vascular disease

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    TETDEDXHerman-temple-0225E-135 ...
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    Genre
    Thesis/Dissertation
    Date
    2019
    Author
    Herman, Allison
    Advisor
    Autieri, Michael V.
    Committee member
    Haines, Dale
    Kilpatrick, Laurie
    Rizzo, Victor
    Eguchi, Satoru
    Youngman, Elaine
    Department
    Biomedical Sciences
    Subject
    Biology, Molecular
    Cellular Biology
    Biology
    Ares
    Atherosclerosis
    Inflammation
    Rna-binding Proteins
    Rna Stability
    Vascular Smooth Muscle Cells
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3000
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2982
    Abstract
    This work identifies the Fragile X-related protein (FXR1) as a reciprocal regulator of HuR target transcripts in vascular smooth muscle cells (VSMC). FXR1 was identified as an HuR interacting protein by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The-HuR-FXR1 interaction is abrogated in RNase-treated extracts, indicating that their association is tethered by mRNAs. FXR1 expression is induced in diseased, but not normal arteries. SiRNA knock down of FXR1 increases abundance and stability of inflammatory mRNAs, while overexpression of FXR1 reduces their abundance and stability. RNA-EMSA and RIP demonstrate that FXR1 directly interacts with an ARE and a previously uncharacterized element in the 3’UTR of TNFa. FXR1 expression is increased in VSMC challenged with the anti-inflammatory cytokine IL-19, and FXR1 is required for IL-19 reduction of HuR. This suggests FXR1 is an anti-inflammation responsive, HuR counter-regulatory protein that reduces abundance of pro-inflammatory transcripts. Additionally, we observed significantly increased poly-A-Binding protein (PABP) expression localizing to discrete punctate structures in both vascular smooth muscle (VSMC) and endothelial cells (EC) of the aortic arch of Ldlr-/- mice, as compared to WT controls. EIF2α phosphorylation, requisite for SG formation, was also induced by clotrimazole and oxLDL in these cells. Interestingly, VSMCs pre-treated with anti-inflammatory cytokine IL-19 followed by clotrimazole significantly reduced the formation of SGs and eIF2a phosphorylation, suggesting a relationship between inflammation and SG formation in vascular cells. Reduction of SG component G3BP1 by siRNA knockdown significantly reduced stress granule formation and inflammatory gene abundance in hVSMC. Microtubule inhibitors reduced SG formation in hVSMC. These results support the hypothesis that SG formation in atherosclerosis is driven by inflammation, SG may mediate the cellular response to inflammation, and that anti-inflammatory treatment may lessen atherosclerosis progression and plaque formation by reduction of SGs.
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