title: P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development.
abstract: BACKGROUND
  P2Y(6), a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y(6) deficiency on atherosclerosis.
  
  
  RESULTS
  Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y(6) receptors, showed that exogenous expression of P2Y(6) induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation. To evaluate the role of P2Y(6) in atherosclerotic lesion development, we used P2Y(6)-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y(6) receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y(6)xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y(6) deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice.
  
  
  CONCLUSIONS
  P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Garcia
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Mujing
authors.initials: M
authors.lastname: Yan
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Search
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Rongan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Carson
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Ryan
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Constance
authors.initials: C
authors.lastname: Smith-Monroy
authors.affiliation: Pharmaceutical Compound Optimization: Discovery Toxicology, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Lead Evaluation, Bristol-Myers Squibb Company, Lawrenceville, New Jersey, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Lead Evaluation, Bristol-Myers Squibb Company, Lawrenceville, New Jersey, United States of America.
authors.forename: Huaping
authors.initials: H
authors.lastname: Tang
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Hellings
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Wardwell-Swanson
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Dinchuk
authors.affiliation: Veterinary Sciences, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: George C
authors.initials: GC
authors.lastname: Psaltis
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.affiliation: Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gargalovic
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011973:Receptors, LDL; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6