Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.

Cardiovascular Research

PubMedID: 25644539

Mahmut A, Boulanger MC, Bouchareb R, Hadji F, Mathieu P. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. Cardiovasc Res. 2015;106(1):109-20.
OBJECTIVES
In this study, we sought to determine the role of ecto-nucleotidases and adenosine receptors in calcific aortic valve disease (CAVD).

BACKGROUND
The expression of ecto-nucleotidases, which modify the levels of extracellular nucleotides/nucleosides, may control the mineralization of valve interstitial cells (VICs). We hypothesized that expression of NPP1, which generates AMP, and 5'nucleotidase (CD73), an enzyme using AMP as a substrate to produce adenosine, may co-regulate the mineralization of the aortic valve.

METHODS
We have investigated the expression of NPP1 and 5'nucleotidase in CAVD tissues and determined the role of these ecto-nucleotidases on the mineralization of isolated VICs.

RESULTS
In CAVD tissues (stenotic and sclerotic) we documented that NPP1 and 5'nucleotidase were overexpressed by VICs. In isolated VICs, we found that mineralization induced by ATP was decreased by silencing NPP1 and 5'nucleotidase, suggesting a role for adenosine. Adenosine and specific A2a adenosine receptor (A2aR) agonist increased the mineralization of VICs. Silencing of A2aR in human VICs and the use of A2aR(-/-) mouse VICs confirmed that A2aR promotes the mineralization of cells. Also, A2aR-mediated mineralization was negated by the transfection of a mutant dominant negative Gas vector. Through several lines of evidence, we next documented that adenosine stimulated the mineralization of VICs through a cAMP/PKA/CREB pathway and found that CREB positively regulated the expression of NPP1 in a positive feedback loop by physically interacting with the promoter.

CONCLUSION
Expression of NPP1 and 5'nucleotidase by VICs promotes the mineralization of the aortic valve through A2aR and a cAMP/PKA/CREB pathway.