Ablajan Mahmut1, Marie-Chloé Boulanger1, Rihab Bouchareb1, Fayez Hadji1, Patrick Mathieu2. 1. Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, Quebec, Canada G1V-4G5. 2. Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, Quebec, Canada G1V-4G5 patrick.mathieu@chg.ulaval.ca.
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 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 Gαs 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 humanVICs and the use of A2aR(-/-) mouseVICs confirmed that A2aR promotes the mineralization of cells. Also, A2aR-mediated mineralization was negated by the transfection of a mutant dominant-negative Gαs 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Brian R Lindman; Marie-Annick Clavel; Patrick Mathieu; Bernard Iung; Patrizio Lancellotti; Catherine M Otto; Philippe Pibarot Journal: Nat Rev Dis Primers Date: 2016-03-03 Impact factor: 52.329
Authors: Patrycja Jablonska; Barbara Kutryb-Zajac; Paulina Mierzejewska; Agnieszka Jasztal; Barbara Bocian; Romuald Lango; Jan Rogowski; Stefan Chlopicki; Ryszard T Smolenski; Ewa M Slominska Journal: J Cell Mol Med Date: 2021-06-18 Impact factor: 5.310
Authors: Barbara Kutryb-Zajac; Ada H Y Yuen; Zain Khalpey; Paulina Zukowska; Ewa M Slominska; Patricia M Taylor; Steven Goldstein; Albert E Heacox; Marialuisa Lavitrano; Adrian H Chester; Magdi H Yacoub; Ryszard T Smolenski Journal: J Cardiovasc Transl Res Date: 2016-02-01 Impact factor: 4.132