Interaction of NADPH oxidase 1 with toll-like receptor 2 induces migration of smooth muscle cells

Jee Hyun Lee, Jung Hee Joo, Jinoh Kim, Hee Jung Lim, Sunah Kim, Linda Curtiss, Je Kyung Seong, Wenhao Cui, Chihiro Yabe-Nishimura, Yun Soo Bae

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Aims NADPH oxidase (Nox) isozymes that generate intracellular reactive oxygen species (ROS) and Toll-like receptor 2 (TLR2), an inflammatory mediator, are both involved in the development of atherosclerotic lesions. To identify the molecular connection between TLR2 and Nox isozymes in vascular remodelling, we analysed generation of ROS and proinflammatory cytokines in aortic smooth muscle cells from Nox1-deficient mice in response to the synthetic triacylated lipoprotein Pam3CSK, a TLR2 agonist. Methods and results We showed that TLR2 signalling stimulates progression of the pro-inflammatory phenotype in mouse aortic smooth muscle cells (MASMCs) through activation of Nox1. We demonstrated the interaction of TLR2 with Nox1 using yeast two-hybrid and co-immunoprecipitation assays. MASMCs from Nox1-deficient mice failed to generate of ROS in response to Pam3CSK4, indicating that Nox1 is essential for TLR2-dependent production of ROS. We also found that Pam3CSK4 stimulated migration of MASMCs from wild-type mice in a Transwell system, but MASMCs from Nox1-deficient mice failed to show this response.Wild-type MASMCs produced matrix metalloprotease 2 in response to Pam3CSK4, whereas Nox1-deficient MASMCs failed to generate this protease. Moreover, stimulation of MASMCs with Pam3CSK4 resulted in increased expression of the pro-inflammatory cytokine macrophage inflammatory protein 2 in a Nox1-dependent manner, leading to enhanced monocyte-endothelial cell adhesion and trans-endothelial migration of U937 cells. Conclusion These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling.

Original languageEnglish
Pages (from-to)483-493
Number of pages11
JournalCardiovascular Research
Volume99
Issue number3
DOIs
StatePublished - 1 Aug 2013

Keywords

  • Macrophage inflammatory protein 2
  • Mouse aortic smooth muscle cells
  • NADPH oxidase
  • Reactive oxygen species
  • Toll-like receptor 2

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