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Title: Andrographolide enhances nuclear factor-κB subunit p65 Ser 536 dephosphorylation through activation of protein phosphatase 2A in vascular smooth muscle cells
Authors: Hsieh, C.Y.;Hsu, M.J.;Hsiao, G.;Wang, Yi-hsuan;Huang, C.W.;Chen, S.W.;Jayakumar, T.;Chiu, P.T.;Chiu, Y.H.;Sheu, J.R.
Contributors: 法律科際整合研究所
Keywords: Andrographolide;Anti-inflammatory action;Ceramides;Dephosphorylations;DNA binding activity;Down-regulation;Injury models;Matrix metalloprotease;Neointimal formation;Nitric-oxide synthase;Nuclear factors;Nuclear translocations;Pro-inflammatory stimuli;Protein phosphatase 2A;Selective inhibition;Sphingomyelinase;Vascular smooth muscle cells;Amides;Cells;Hydrolases;Lead oxide;Muscle;Phosphatases;Phosphorylation;Signaling;Transcription factors;Blood vessel prostheses;andrographolide;ceramide;DNA;gamma interferon;gelatinase B;I kappa B alpha;I kappa B kinase;inducible nitric oxide synthase;lipopolysaccharide;phosphoprotein phosphatase 2A;serine;sphingomyelin phosphodiesterase;transcription factor RelA;animal cell;animal experiment;animal model;animal tissue;article;carotid artery injury;controlled study;down regulation;drug effect;drug mechanism;enzyme activation;enzyme activity;male;neointima;nonhuman;priority journal;protein degradation;protein dephosphorylation;protein DNA binding;protein expression;protein phosphorylation;protein transport;rat;reporter gene;signal transduction;smooth muscle fiber;vascular smooth muscle;Active Transport, Cell Nucleus;Andrographis;Animals;Anti-Inflammatory Agents, Non-Steroidal;Cell Nucleus;Ceramides;Diterpenes;Enzyme Activation;Interferon-gamma;Lipopolysaccharides;Male;Matrix Metalloproteinase 9;Muscle, Smooth, Vascular;Myocytes, Smooth Muscle;Nitric Oxide Synthase Type II;Phosphorylation;Protein Phosphatase 2;Rats;Rats, Wistar;Serine;Sphingomyelin Phosphodiesterase;Transcription Factor RelA;Andrographis;Rattus
Date: 2011-02
Issue Date: 2015-05-29 16:54:58 (UTC+8)
Abstract: Recent studies have demonstrated that transcription factor nuclear factor (NF)-κB inhibition may contribute to the protective anti-inflammatory actions of andrographolide, an abundant component of plants of the genus Andrographis. However, the precise mechanism by which andrographolide inhibits NF-κB signaling remains unclear. We thus investigated the mechanism involved in andrographolide suppression of NF-κB signaling in rat vascular smooth muscle cells (VSMCs) exposed to proinflammatory stimuli, LPS, and IFN-γ. Andrographolide was shown to suppress LPS/IFN-γ-induced inducible nitric-oxide synthase and matrix metalloprotease 9 expression in rat VSMCs. Andrographolide also inhibited LPS/IFN-γ-induced p65 nuclear translocation, DNA binding activity, p65 Ser536 phosphorylation, and NF-κB reporter activity. However, IKK phosphorylation and downstream inhibitory κBα phosphorylation and degradation were not altered by the presence of andrographolide in LPS/IFN-γ-stimulated VSMCs. These andrographolide inhibitory actions could be prevented by selective inhibition of neutral sphingomyelinase and protein phosphatase 2A (PP2A). Furthermore, andrographolide was demonstrated to increase ceramide formation and PP2A activity in VSMCs and to inhibit neointimal formation in rat carotid injury models. These results suggest that andrographolide caused neutral sphingomyelinase-mediated ceramide formation and PP2A activation to dephosphorylate p65 Ser536, leading to NF-κB inactivation and subsequent inducible nitric-oxide synthase down-regulation in rat VSMCs stimulated by LPS and IFN-γ. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Relation: Journal of Biological Chemistry, 286(8), 5942-5955
Data Type: article
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