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- Title
Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor.
- Authors
Mahmut, Ablajan; Boulanger, Marie-Chloé; Bouchareb, Rihab; Hadji, Fayez; Mathieu, Patrick
- Abstract
Aims In this study, we sought to determine the role of ecto-nucleotidases and adenosine receptors in calcific aortic valve disease (CAVD). 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 ectonucleotide pyrophosphatase/ phosphodiesterase 1 (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 and results We have investigated the expression of NPP1 and 5'-nucleotidase in CAVD tissues and determined the role of these ectonucleotidases on the mineralization of isolated VICs. 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 adenosine triphosphate 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 A2aR2/2 mouse VICs confirmed that A2aR promotes the mineralization of cells. Also, A2aR-mediated mineralizationwas 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/protein kinase A (PKA)/ cAMP response element-binding protein (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.
- Subjects
ADENOSINES; NUCLEOTIDASES; AORTIC valve; ADENOSINE kinase; BIOMINERALIZATION; PROTEIN kinases
- Publication
Cardiovascular Research, 2015, Vol 106, Issue 1, p109
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvv027