Nod1 Ligands Induce Site-Specific Vascular Inflammation

DOI HANDLE Web Site 21 Citations 34 References Open Access
  • Nishio, Hisanori
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University | Department of Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University
  • Kanno, Shunsuke
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University
  • Onoyama, Sagano
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University
  • Ikeda, Kazuyuki
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University
  • Tanaka, Tamami
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University
  • Kusuhara, Koichi
    Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health
  • Fujimoto, Yukari
    Department of Chemistry, Graduate School of Science, Osaka University
  • Fukase, Koichi
    Department of Chemistry, Graduate School of Science, Osaka University
  • Sueishi, Katsuo
    Department of Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University
  • Hara, Toshiro
    Japan Society for the Promotion of Science | Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University

Abstract

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/cytokine and matrix metallopeptidase ( <jats:italic>Mmp</jats:italic> ) genes in each tissue in vivo by microarray analysis. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion—</jats:title> <jats:p>This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1 ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans.</jats:p> </jats:sec>

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