Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages

Laura Moreno, S.K. McMaster, T. Gatheral, Louise Harrington, N. Cartwright, P.C.J. Armstrong, Timothy D. Warner, Mark Paul-Clark, Jane Mitchell

Research output: Contribution to journalArticle

Abstract

Background and purpose: Gram-negative bacteria contain ligands for Toll-like receptor (TLR) 4 and nucleotide oligomerizationdomain (NOD) 1 receptors. Lipopolysaccharide (LPS) activates TLR4, while peptidoglycan products activate NOD1.Activation of NOD1 by the specific agonist FK565 results in a profound vascular dysfunction and experimental shock in vivo.Experimental approach: Here, we have analysed a number of pharmacological inhibitors to characterize the role of keysignalling pathways in the induction of NOS2 following TLR4 or NOD1 activation.Key results: Vascular smooth muscle (VSM) cells expressed NOD1 mRNA and protein, and, after challenge with Escherichia colior FK565, NOS2 protein and activity were induced. Macrophages had negligible levels of NOD1 and were unaffected byFK565, but responded to E. coli and LPS by releasing increased NO and expression of NOS2 protein. Classic pharmacologicalinhibitors for NF-kB (SC-514) and mitogen-activated protein kinase (SB203580, PD98059) signalling pathways inhibitedresponses in both cell types regardless of agonist. While TLR4-mediated responses in macrophages were specifically inhibitedby the pan-caspase inhibitor z-VAD-fmk and the PKC inhibitor Gö6976, NOD1-mediated responses in VSM cells were inhibitedby the Rip2 inhibitor PP2.Conclusions and implications: Our findings suggest a selective role for NOD1 in VSM cells, and highlight NOD1 as a potentialnovel therapeutic target for the treatment of vascular inflammation.
Original languageEnglish
Pages (from-to)1997-2007
Number of pages11
JournalBritish Journal of Pharmacology
Volume160
DOIs
Publication statusPublished - 1 Aug 2010

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