Merck
  • P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.

P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.

Arteriosclerosis, thrombosis, and vascular biology (2014-08-12)
Peter Stachon, Alexander Peikert, Nathaly Anto Michel, Sonja Hergeth, Timoteo Marchini, Dennis Wolf, Bianca Dufner, Natalie Hoppe, Cemil Korcan Ayata, Melanie Grimm, Sanja Cicko, Lisa Schulte, Jochen Reinöhl, Constantin von zur Muhlen, Christoph Bode, Marco Idzko, Andreas Zirlik
摘要

Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. 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 low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.

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Sigma-Aldrich
单克隆抗 FITC-生物素 小鼠抗, clone FL-D6, purified immunoglobulin, buffered aqueous solution