NOD1 ligand FK565 promotes atherogenesis and accumulation of NOD1highsmooth muscle cells in atherosclerotic lesions

Aims Nucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. Methods and results NOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) pathways, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1 high SMC were also found in arteries of atherosclerosis-prone Ldlr −/− mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1 high SMC expansion and neointima formation. In vitro , neointima derived NOD1 high SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS + cells and amplified CCL5 production. Conclusion Our findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1 high subtype of SMC.