Activation of the adenosine-A3 receptor stimulates matrix metalloproteinase-9 secretion by macrophages.
OBJECTIVE
Matrix metalloproteinase-9 (MMP-9) plays an important role in ventricular remodelling after acute myocardial infarction (MI). The cardioprotectant adenosine (Ado) may be involved in ventricular remodelling. We have shown that Ado inhibits the secretion of MMP-9 by human neutrophils. This study investigated the effect of Ado on MMP-9 production by human macrophages.


RESULTS
Cells used in this study were monocytes of healthy volunteers, a human monocyte cell line, and leukocytes from patients following MI. Monocytes were differentiated into macrophages and treated with Ado. Ado enhanced MMP-9 secretion by human macrophages in a time- and dose-dependent manner. Increasing the level of endogenous Ado by inhibition of Ado deaminase or Ado transferase also increased MMP-9 secretion. Ado enhanced MMP-9 production when macrophages were activated by hypoxia or Toll-like receptor-4 ligands such as lipopolysaccharide, hyaluronan, and heparan sulfate. The effect of Ado was replicated by the A3 agonist IB-MECA and inhibited by silencing the A3 receptor. Ado improved monocyte capacity to migrate through a matrix of gelatin B, and this effect was blocked by inhibition of MMP-9 activity. The chemotactic capacity of macrophages was reduced by Ado through a loss of expression of the monocyte chemotactic protein-1 receptor. Finally, MMP-9 expression was higher in blood cells from patients with acute MI compared with healthy volunteers.


CONCLUSIONS
Adenosine activates MMP-9 secretion by macrophages through its A3 receptor. The effect is in contrast to that observed in neutrophils, where Ado inhibits MMP-9 secretion by the A2a receptor. These observations may have important implications for therapeutic strategies targeting Ado receptors in the setting of MI.
Velot
Emilie
E
Laboratory of Cardiovascular Research, CRP-Santé, Luxembourg, Luxembourg.
Haas
Benjamin
B
Léonard
Frédérique
F
Ernens
Isabelle
I
Rolland-Turner
Magali
M
Schwartz
Chantal
C
Longrois
Dan
D
Devaux
Yvan
Y
Wagner
Daniel R
DR
D000241:Adenosine / Q000378:metabolism*; D058909:Adenosine A3 Receptor Agonists; D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005780:Gelatin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation
D058909:Adenosine A3 Receptor Agonists; D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043684:Receptor, Adenosine A3; C495345:TLR4 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D051197:Toll-Like Receptor 4; D005780:Gelatin; D020780:Matrix Metalloproteinase 9; D000243:Adenosine Deaminase; D000241:Adenosine