Cardiovascular Research Advance Access first published online on July 24, 2008
This version [Corrected Proof] published online on August 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn201
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Activation of the adenosine-A3 receptor stimulates matrix metalloproteinase-9 secretion by macrophages
1 Laboratory of Cardiovascular Research, CRP-Santé, Luxembourg, Luxembourg
2 Department of Anesthesia and Intensive Care, Centre Hospitalier Universitaire de Nancy, France
3 INSERM U684, Université Henri Poincaré Nancy I, France
4 Division of Cardiology, Centre Hospitalier Luxembourg, 4 rue Barblé, L1210 Luxembourg, Luxembourg
* Corresponding author. Tel: +352 44 11 2221; fax: +352 44 11 6629. E-mail address: wagner.daniel{at}chl.lu
Aims: 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.
Methods and 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.
Conclusion: 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.
KEYWORDS Adenosine; Monocytes/macrophages; Ventricular remodelling; Matrix metalloproteinase-9; Cell migration
Time for primary review: 29 days
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