Adenosine receptor A2A deficiency in leukocytes increases arterial neointima formation in apolipoprotein E-deficient mice.
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.
Wang
Huan
H
Department of Medicine, University of Minnesota, Minneapolis, USA.
Zhang
Weiyu
W
Tang
Rong
R
Zhu
Chuhong
C
Bucher
Christoph
C
Blazar
Bruce R
BR
Geng
Jian-Guo
JG
Zhang
Chunxiang
C
Linden
Joel
J
Wu
Chaodong
C
Huo
Yuqing
Y
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
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