Objective: Nucleotides such as ATP, ADP, UTP, and UDP serve as pro- inflammatory danger signals via purinergic receptors upon their release to the extracellular space by activated or dying cells. UDP binds to the P2Y6 receptor and propagates vascular inflammation by inducing the expression of chemokines such as MCP-1, IL-8 and adhesion molecules such as VCAM-1 and ICAM-1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Since atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall we hypothesized a role of P2Y6 in atherogenesis.
Approach and Results: Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of LDLR-/- mice consuming high cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6-/-/LDLR-/- mice consuming high cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6+/+/LDLR-/- mice. Atherosclerotic lesions of P2Y6- deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA-Expression of VCAM-1 and IL-6 was decreased in these lesions.
Conclusions: We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.