Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe2/2 mice

Shunsuke Kanno, Hisanori Nishio, Tamami Tanaka, Yoshitomo Motomura, Kenji Murata, Kenji Ihara, Mitsuho Onimaru, Sho Yamasaki, Hajime Kono, Katsuo Sueishi, Toshiro Hara

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31 Citations (Scopus)


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 Apoe2/2 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.

Original languageEnglish
Pages (from-to)773-780
Number of pages8
JournalJournal of Immunology
Issue number2
Publication statusPublished - Jan 15 2015

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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