| First Author | Mahmut A | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 106 |
| Issue | 1 | Pages | 109-20 |
| PubMed ID | 25644539 | Mgi Jnum | J:250701 |
| Mgi Id | MGI:6104928 | Doi | 10.1093/cvr/cvv027 |
| Citation | Mahmut A, et al. (2015) Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. Cardiovasc Res 106(1):109-20 |
| abstractText | 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 ecto-nucleotidases 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 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 Galphas 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. |
