title: Adenosine receptor A2A deficiency in leukocytes increases arterial neointima formation in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  To use the mice deficient in both adenosine receptor A(2A)(A(2A)R(-/-)) and apolipoprotein E (apoE(-/-)) to investigate the role of A(2A)R in mediating the interactions of leukocytes with injured arterial walls and the formation of arterial neointima induced by a guide wire.
  
  
  RESULTS
  In apoE(-/-) mice, A(2A)R deficiency increased the size of the arterial neointima in injured carotid arteries by 83%. Arterial neointima formation was also enhanced in chimeric mice that underwent bone marrow transplantation (these mice lacked A(2A)R in their bone marrow-derived cells). Epifluorescence intravital microscopy showed that neutrophil rolling and adherence to the injured arterial area were enhanced by 80% and 110% in A(2A)R(-/-)/apoE(-/-) mice, respectively. This phenomenon occurred even though the protein levels of homing molecules on A(2A)R-deficient neutrophils were unchanged from those of wild-type neutrophils. A(2A)R-deficient neutrophils exhibited an increase in the phosphorylation of p38 mitogen-activated protein kinase, P-selectin glycoprotein ligand-1 (PSGL-1) clustering, and the affinity of b(2) integrins. The inhibition of p38 phosphorylation abrogated the increased PSGL-1 clustering and beta(2) integrin affinity, thus reversing the increased homing ability of A(2A)R-deficient leukocytes.
  
  
  CONCLUSIONS
  A(2A)R plays a complex role in inflammation and tissue injury. The deficiency of A(2A)R enhances the homing ability of leukocytes and increases the formation of the arterial neointima after injury. A(2A)R antagonists are being tested for the treatment of neurodegenerative and other chronic diseases. An evaluation of the effect of A(2A)R antagonists on arterial restenosis after arterial angioplasty should be conducted.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Weiyu
authors.initials: W
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Tang
authors.forename: Chuhong
authors.initials: C
authors.lastname: Zhu
authors.forename: Christoph
authors.initials: C
authors.lastname: Bucher
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Geng
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Zhang
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006965:Hyperplasia; D036904:Leukocyte Rolling; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018821:CD18 Antigens; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D047428:Protein Kinase Inhibitors; D043705:Receptor, Adenosine A2A; D048051:p38 Mitogen-Activated Protein Kinases