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Adenosine inhibits matrix metalloproteinase-9 secretion by neutrophils: implication of A2a receptor and cAMP/PKA/Ca2+
Isabelle Ernens1, Didier Rouy, Emilie Velot
1Laboratory of Cardiovascular Research, CRP-Santé, Luxembourg.
Abstract:
Matrix metalloproteinases (MMPs), and in particular MMP-9 secreted by neutrophils, are capable of degrading the matrix components of the heart and are thought to be the driving force behind myocardial matrix remodeling after infarction. Adenosine, a naturally produced nucleoside, has been shown to have cardioprotective effects and to inhibit secretion of various cytokines. The aim of our study was to determine the effect of adenosine on the secretion of MMP-9 by neutrophils. Neutrophils were isolated from healthy volunteers through Ficoll and Dextran sedimentation. Neutrophils were activated by N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence or absence of adenosine or adenosine analogs. Zymography and enzyme linked immunosorbent assay were used to measure MMP-9 secretion. Adenosine (1 micromol/L) decreased the fMLP-induced MMP-9 secretion by 30+/-2% (n=8, P<0.001). The effect was dose-dependent and was not specific to fMLP because adenosine also inhibited MMP-9 secretion by LPS- or H(2)O(2)-stimulated neutrophils. The effect of adenosine was mimicked by the adenosine A2a receptor agonist CGS21680 and was inhibited by both the A2a antagonist SCH5826 and A2a RNA silencing. The A3 agonist IB-MECA moderately decreased fMLP-induced MMP-9 secretion. Agonists and antagonists of the other types of adenosine receptors had no significant effect. Adenosine increased intracellular cAMP concentration and accelerated the return to baseline of the intracytoplasmic calcium peak. The inhibition of MMP-9 secretion by adenosine, as well as the calcium effect, was prevented by the protein kinase A inhibitor H-89. In conclusion, we show here that adenosine inhibits MMP-9 secretion by neutrophils. Our results suggest that this effect implies the A2a receptor and is mediated through the cAMP/PKA/Ca(2+) pathway. Therefore, adenosine may represent a new approach to prevent matrix degradation and remodeling after myocardial injury.
Insights
Adenosine, a natural compound, significantly reduces the secretion of matrix metalloproteinase-9 (MMP-9) from neutrophils. This finding suggests adenosine
Area of Science:
- Cardiovascular Research
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs), particularly MMP-9 from neutrophils, degrade heart matrix components, driving post-infarction remodeling.
- Adenosine, a naturally occurring nucleoside, exhibits cardioprotective properties and can inhibit cytokine secretion.
Purpose of the Study:
- To investigate the effect of adenosine on neutrophil-mediated MMP-9 secretion.
- To elucidate the specific adenosine receptor and intracellular pathways involved in this modulation.
Main Methods:
- Neutrophil isolation from healthy volunteers.
- Stimulation of neutrophils with fMLP, LPS, or H2O2 in the presence or absence of adenosine or its analogs.
- Quantification of MMP-9 secretion using zymography and ELISA.
- Assessment of intracellular cAMP levels and calcium signaling dynamics.
- Pharmacological inhibition and RNA silencing targeting adenosine receptors and protein kinase A (PKA).
Main Results:
- Adenosine significantly inhibited fMLP-induced MMP-9 secretion in a dose-dependent manner (30% reduction at 1 micromol/L).
- This inhibitory effect was observed with LPS- and H2O2-stimulated neutrophils, indicating a general mechanism.
- The adenosine A2a receptor agonist CGS21680 mimicked the effect, while the A2a antagonist SCH5826 and A2a RNA silencing blocked it.
- Adenosine increased intracellular cAMP and modulated calcium signaling, effects mediated via the cAMP/PKA/Ca(2+) pathway.
Conclusions:
- Adenosine effectively inhibits neutrophil MMP-9 secretion through the A2a receptor.
- The mechanism involves the cAMP/PKA/Ca(2+) signaling pathway.
- Adenosine holds potential as a therapeutic agent to prevent matrix degradation and remodeling following myocardial injury.
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