title: Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice.
abstract: Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo. To investigate a potential role of NOD1 in atherogenesis, we orally administered FK565 to apolipoprotein E knockout (Apoe(-/-)) mice for 4 wk intermittently and performed quantification of atherosclerotic lesions in aortic roots and aortas, immunohistochemical analyses, and microarray-based gene expression profiling of aortic roots. FK565 administration accelerated the development of atherosclerosis in Apoe(-/-) mice, and the effect was dependent on Nod1 in non-bone marrow origin cells by bone marrow transplantation experiments. Immunohistochemical studies revealed the increases in the accumulation of macrophages and CD3 T cells within the plaques in aortic roots. Gene expression analyses of aortic roots demonstrated a marked upregulation of the Ccl5 gene during early stage of atherogenesis, and the treatment with Ccl5 antagonist significantly inhibited the acceleration of atherosclerosis in FK565-administered Apoe(-/-) mice. Additionally, as compared with Apoe(-/-) mice, Apoe and Nod1 double-knockout mice showed reduced development of atherosclerotic lesions from the early stage as well as their delayed progression and a significant reduction in Ccl5 mRNA levels at 9 wk of age. Data in the present study show that the Nod1 signaling pathway in non-bone marrow-derived cells contributes to the development of atherosclerosis.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; kannos@pediatr.med.kyushu-u.ac.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka 812-8582, Japan;
authors.forename: Hisanori
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Tamami
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University 812-8582, Fukuoka, Japan;
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Motomura
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Murata
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Division of Pathophysiological and Experimental Pathology, Department of Pathology, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University 812-8582, Fukuoka, Japan;
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan; and.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kono
authors.affiliation: Department of Research and Education, National Hospital Organization Fukuoka-Higashi Medical Center, Fukuoka 811-3195, Japan.
authors.forename: Katsuo
authors.initials: K
authors.lastname: Sueishi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D001057:Apolipoproteins E; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D009842:Oligopeptides; C039537:heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine