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. Conclusion-This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1ligand. 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. Key Words: coronary artery disease Ⅲ immune system Ⅲ Kawasaki disease Ⅲ pathology Ⅲ coronary arteritis Ⅲ inflammation G erm-line encoded pattern-recognition receptors of the innate immune system sense exogenous microbial components and endogenous danger signals to protect the host. [1][2][3][4] The pattern-recognition receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors, the leucine-rich repeat-containing (NLR) protein family, and as-yet-unidentified pattern-recognition receptors that recognize double-stranded DNA. 1,3 The TLR, RIG-I-like receptor, and NLR families consist of 10 (human), 3, and more than 20 members, respectively. 1,3,4 In the cardiovascular system, endothelial cells are usually the first among the structural cells to sense microbial components through pattern-recognition receptors. Human endothelial cells express functional innate immune receptors, such as TLRs and NLRs. 5,6 There is a line of evidence that activation of TLRs, especially TLR4 and TLR2, contributes to the development and progression of cardiovascular diseases, including atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure. 7 With respect to NLRs, only a limited number of studies have shown that human endothelial cells express functional NLRs, nucleotide-binding oligomerization domain 1 (NOD1) and NOD2. Chlamydophila pneumoniae and Listeria monocytogenes elicited NOD1-dependent interleukin (IL)-8 production in endothelial cells. 8,9 A selective NOD1 ligand, FK565, ...

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

“…In this study, the NOD1 ligand induced MMP9 gene expression and secretion of pro MMP9 from both subcutaneous and omental adipose tissues. Similarly, NOD1 has been shown to induce MMP9 in human placenta (Lappas 2013b), and in vivo in the aortic root and pulmonary artery after oral administration of a NOD1 ligand (Nishio et al 2011).…”

“…This is the first study, to my knowledge, to report that NOD1 activation upregulates the adhesion molecules in adipose tissue. However, ligand activation of NOD1 has been shown to increase ICAM1 gene expression in human airway smooth muscle cells (Kvarnhammar et al 2013), bronchial epithelial cells (Wong et al 2013) and human coronary artery endothelial cells (Nishio et al 2011). In vivo, NOD1 ligands induce ICAM1 and VCAM1 gene expression in the aortic root, pulmonary artery, aorta and spleen (Nishio et al 2011).…”

Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy

“…This study found that the Nod1 signaling pathway in fetuses contributed to vascular responses and IUGR. Further study is required to determine whether stressful conditions in utero could be a risk for vasculopathy in young (13) and adult mice (14). Further study is required to examine whether Nod1 ligand-induced vasculopathy during fetal life would lead to an increased susceptibility to cardiovascular diseases in adulthood.…”

“…3A-C). In this study, we used the same line of Nod1-knockout mice that was previously reported (13,14). FK565 does not induce inflammation in Nod1-knockout mice.…”

“…Recently, we demonstrated a specific role of Nod1 in the development of acute vascular inflammation in young mice (13) and atherosclerosis in adult mice (14). On the other hand, the effects of the activation of Nod1 in the fetuses or in newborns have been poorly understood (15)(16)(17).…”