title: P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.
abstract: OBJECTIVE
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Peter
authors.initials: P
authors.lastname: Stachon
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Peikert
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Nathaly Anto
authors.initials: NA
authors.lastname: Michel
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Sonja
authors.initials: S
authors.lastname: Hergeth
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Timoteo
authors.initials: T
authors.lastname: Marchini
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Bianca
authors.initials: B
authors.lastname: Dufner
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Natalie
authors.initials: N
authors.lastname: Hoppe
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Cemil Korcan
authors.initials: CK
authors.lastname: Ayata
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Melanie
authors.initials: M
authors.lastname: Grimm
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Sanja
authors.initials: S
authors.lastname: Cicko
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Schulte
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Jochen
authors.initials: J
authors.lastname: Reinöhl
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Constantin
authors.initials: C
authors.lastname: von zur Muhlen
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.). andreas.zirlik@universitaets-herzzentrum.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D036904:Leukocyte Rolling; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D018836:Inflammation Mediators; D011973:Receptors, LDL; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate
keywords: P2Y6 receptor; atherosclerosis; inflammation; receptors, purinergic P2; uridine diphosphate; vascular cell adhesion molecule-1