title: Deletion of P2Y2 receptor reveals a role for lymphotoxin-α in fatty streak formation.
abstract: Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction. Activation of the P2Y2 nucleotide receptor (P2Y2R) regulates the production of LTα. in vitro. We aimed to uncover a potential pathway linking purinergic receptor to LTα-mediated inflammatory processes pivotal to the early stages of atherosclerosis in apolipoprotein E (ApoE(-)(/)(-)) deficient mice.
  
  
  
  En face immunostaining revealed that P2Y2R and VCAM-1 are preferentially expressed in the atherosclerosis prone site of the mouse aortic sinus. Deletion of the P2Y2R gene suppresses VCAM-1 expression. Compared with ApoE(-)(/)(-) mice, ApoE(-)(/)(-) mice lacking the P2Y2R gene (ApoE(-)(/)(-)/P2Y2R(-)(/)(-)) did not develop fatty streak lesions when fed a standard chow diet for 15weeks. Systemic and CD4(+) T cell production of the pro-inflammatory cytokine lymphotoxin-alpha (LTα) were specifically inhibited in ApoE(-)(/)(-)/P2Y2R(-)(/)(-)mice. Anti-LTα preventive treatment was initiated in ApoE(-)(/)(-)mice with intraperitoneal administration of recombinant human tumor necrosis factor receptor 1 fusion protein (TNFR1-Fc) on 5 consecutive days before the disease onset. Remarkably, none of the TNFR1:Fc-treated ApoE(-)(/)(-)mice exhibited atherosclerotic lesions at any developmental stage.
  
  
  
  ApoE(-)(/)(-) mice deficient in P2Y2R exhibit low endothelial cell VCAM-1 levels, decreased production of LTα and delayed onset of atherosclerosis. These data suggest that targeting this nucleotide receptor could be an effective therapeutic approach in atherosclerosis.
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive MS 332, Indianapolis, IN 46202, United States.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Qian
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive MS 332, Indianapolis, IN 46202, United States.
authors.forename: April
authors.initials: A
authors.lastname: Hoggatt
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, 725 Harrison Street VPTH 124, West Lafayette, IN 47907-2027, United States.
authors.forename: Yava L
authors.initials: YL
authors.lastname: Jones-Hall
authors.affiliation: Sanford-Burnham Medical Institute, La Jolla, CA 92037, United States.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive MS 332, Indianapolis, IN 46202, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Herring
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive MS 332, Indianapolis, IN 46202, United States. Electronic address: cseye@iu.edu.
authors.forename: Cheikh I
authors.initials: CI
authors.lastname: Seye
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000008:administration & dosage / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D008233:Lymphotoxin-alpha; D058473:Receptors, Purinergic P2Y2; D047888:Receptors, Tumor Necrosis Factor, Type I; D019010:Vascular Cell Adhesion Molecule-1