title: Regulation of MMP-9 expression by the A2b adenosine receptor and its dependency on TNF-α signaling.
abstract: OBJECTIVE
  Macrophage- and vascular-derived matrix metalloproteinase (MMP)-9 plays an important role in neointima formation after vascular injury. The A2b adenosine receptor (A2bAR) elevates cyclic adenosine monophosphate and suppresses tumor necrosis factor-α (TNF-α) levels at baseline and after vascular injury. Considering the influences of TNF-α on MMP-9 expression and activity, here we examined the effect of the A2bAR on the expression of MMP-9 and its potential dependency on TNF-α.
  
  
  METHODS
  We applied protein activity and mRNA analyses of MMP-9 in macrophages derived from A2bAR knockout (KO) and TNF-α receptor KO mice. We employed guidewire-induced femoral artery injuries on A2bAR KO and control mice and analyzed by immunohistochemistry MMP-9 expression in the neointima area.
  
  
  RESULTS
  MMP-9 activity is somewhat less in resident A2bAR KO macrophages compared with wild-type cells. However, MMP-9 is increased in activated macrophages from A2bAR KO when TNF-α is further elevated, or in wild-type cells after TNF-α treatment. In accordance, A2bAR activation downregulates MMP-9 expression in wild-type macrophages, which is ablated in TNF-α receptor KO cells. A greater vascular lesion after femoral artery injury in A2bAR KO mice is associated with elevated TNF-α levels and augmented MMP-9, compared to control mice.
  
  
  CONCLUSIONS
  Ablation of the A2bAR in activated macrophages increases MMP-9. A2bAR activation reduces MMP-9 expression, which depends on TNF-α and could contribute to the protective role of A2bAR in a vascular injury model.
authors.affiliation: Departments of Medicine and Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Chen
authors.forename: Milka
authors.initials: M
authors.lastname: Koupenova
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.forename: Siddika Selva
authors.initials: SS
authors.lastname: Sume
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D043704:Receptor, Adenosine A2B; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9