Nod1 ligands induce site-specific vascular inflammation.

Abstract

OBJECTIVE:

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.

METHODS AND RESULTS:

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 (Mmp) genes in each tissue in vivo by microarray analysis.

CONCLUSIONS:

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.

• Authors: Hisanori Nishio, Shunsuke Kanno, Sagano Onoyama, Kazuyuki Ikeda, Tamami Tanaka, Koichi Kusuhara, Yukari Fujimoto, Koichi Fukase, Katsuo Sueishi, Toshiro Hara
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 5 Pg. 1093-9 (May 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21330608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Cytokines
• Inflammation Mediators
• Ligands
• NOD1 protein, human
• Nod1 Signaling Adaptor Protein
• Nod1 protein, mouse
• Oligopeptides
• Toll-Like Receptors
• Intercellular Adhesion Molecule-1
• Matrix Metalloproteinases
• heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine

Topics

• Animals
• Arteritis (chemically induced, genetics, immunology, metabolism, pathology)
• Cells, Cultured
• Chemokines (genetics, metabolism)
• Coronary Vessels (drug effects, immunology, metabolism, pathology)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, immunology, metabolism, pathology)
• Female
• Gene Expression Profiling (methods)
• Humans
• Immunity, Innate (drug effects)
• Inflammation Mediators (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Ligands
• Matrix Metalloproteinases (genetics, metabolism)
• Mice
• Mice, Inbred Strains
• Nod1 Signaling Adaptor Protein (agonists, metabolism)
• Oligonucleotide Array Sequence Analysis
• Oligopeptides
• Organ Culture Techniques
• Toll-Like Receptors (metabolism)