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• W2043719962 abstract "IntroductionCalcified aortic stenosis (AS) a common valve disease in developed countriess, is the first cause for surgical valve replacement. Similarities in the mechanisms of aortic valve (AV) calcification and processes involed in bone mineralization have come to light. Like bone cells, valvular interstitial cells (VICs) can liberate ATP in the pericellular environment. Consequently, ATP could stimulate purinergic receptors (P2) and ectonucleotidases and therefore control AV calcification.Methods and resultsA tissue-based microarray experiment and real-time PCR (qPCR) analyses revealed that only ectonucleotidase ENPP1 is strongly up-regulated in calcified AV and VICs. In an in vitro model of calcified VICs with 2mM NaH2PO4, ENPP1 inhibition, with ARL67156, reduced significantly mineralization induced by both NaH2PO4 and the transfection with pCMV ENPP1 (P < 0.0001). Moreover, a treatment of VICs with a siRNA for ENPP1 reduced transcript levels as well as enzymatic activity and significantly decreased mineralization of VICs. In VICs, qPCR analyses demonstrated the presence of several P2X (1,4,5,6,7), P2Y (1,2) receptors, and two P1 adenosine receptors (2a, 2b). Inhibition of P2X (isoPPADS) and adenosine receptors (CGS 15943) did not modify the mineralization of VICs, however suramin, a general purinergic receptor antagonist, markedly increased calcification. Treatment of cells with the P2Y2 agonist, 2-thioUTP, reduced calcification significantly (P < 0.0001). Similarly, VICs calcification strongly increased with a P2Y2 siRNA. Treatment of VICs with the calcifying medium increased the transcripts of Runx2, osteocalcin and osteonectin, whereas the addition of ARL67156 or 2-thioUTP prevented this response. In isolated VICs, LY294002, a PI3K inhibitor, significantly increased the calcification of VICs and antagonized the protective effect of P2Y2 agonist. Tunel staining showed reduced apoptotic cells with ARL 67156 and 2-thioUTP but LY294002 negated this effect (P ANOVA<0.0001). Finally, rats treated with warfarin developed AS and a significant rise of transaortic velocity, whereas the treatment with ARL67156 prevented the appearance of a stenosis.ConclusionResults acquired in this study indicate that biodisponibility of ATP is a crucial signal for survival or death of VICs and plays an important role in AS development. Hence, present findings offer novel therapeutic opportunities for the treatment of CAVD. IntroductionCalcified aortic stenosis (AS) a common valve disease in developed countriess, is the first cause for surgical valve replacement. Similarities in the mechanisms of aortic valve (AV) calcification and processes involed in bone mineralization have come to light. Like bone cells, valvular interstitial cells (VICs) can liberate ATP in the pericellular environment. Consequently, ATP could stimulate purinergic receptors (P2) and ectonucleotidases and therefore control AV calcification. Calcified aortic stenosis (AS) a common valve disease in developed countriess, is the first cause for surgical valve replacement. Similarities in the mechanisms of aortic valve (AV) calcification and processes involed in bone mineralization have come to light. Like bone cells, valvular interstitial cells (VICs) can liberate ATP in the pericellular environment. Consequently, ATP could stimulate purinergic receptors (P2) and ectonucleotidases and therefore control AV calcification. Methods and resultsA tissue-based microarray experiment and real-time PCR (qPCR) analyses revealed that only ectonucleotidase ENPP1 is strongly up-regulated in calcified AV and VICs. In an in vitro model of calcified VICs with 2mM NaH2PO4, ENPP1 inhibition, with ARL67156, reduced significantly mineralization induced by both NaH2PO4 and the transfection with pCMV ENPP1 (P < 0.0001). Moreover, a treatment of VICs with a siRNA for ENPP1 reduced transcript levels as well as enzymatic activity and significantly decreased mineralization of VICs. In VICs, qPCR analyses demonstrated the presence of several P2X (1,4,5,6,7), P2Y (1,2) receptors, and two P1 adenosine receptors (2a, 2b). Inhibition of P2X (isoPPADS) and adenosine receptors (CGS 15943) did not modify the mineralization of VICs, however suramin, a general purinergic receptor antagonist, markedly increased calcification. Treatment of cells with the P2Y2 agonist, 2-thioUTP, reduced calcification significantly (P < 0.0001). Similarly, VICs calcification strongly increased with a P2Y2 siRNA. Treatment of VICs with the calcifying medium increased the transcripts of Runx2, osteocalcin and osteonectin, whereas the addition of ARL67156 or 2-thioUTP prevented this response. In isolated VICs, LY294002, a PI3K inhibitor, significantly increased the calcification of VICs and antagonized the protective effect of P2Y2 agonist. Tunel staining showed reduced apoptotic cells with ARL 67156 and 2-thioUTP but LY294002 negated this effect (P ANOVA<0.0001). Finally, rats treated with warfarin developed AS and a significant rise of transaortic velocity, whereas the treatment with ARL67156 prevented the appearance of a stenosis. A tissue-based microarray experiment and real-time PCR (qPCR) analyses revealed that only ectonucleotidase ENPP1 is strongly up-regulated in calcified AV and VICs. In an in vitro model of calcified VICs with 2mM NaH2PO4, ENPP1 inhibition, with ARL67156, reduced significantly mineralization induced by both NaH2PO4 and the transfection with pCMV ENPP1 (P < 0.0001). Moreover, a treatment of VICs with a siRNA for ENPP1 reduced transcript levels as well as enzymatic activity and significantly decreased mineralization of VICs. In VICs, qPCR analyses demonstrated the presence of several P2X (1,4,5,6,7), P2Y (1,2) receptors, and two P1 adenosine receptors (2a, 2b). Inhibition of P2X (isoPPADS) and adenosine receptors (CGS 15943) did not modify the mineralization of VICs, however suramin, a general purinergic receptor antagonist, markedly increased calcification. Treatment of cells with the P2Y2 agonist, 2-thioUTP, reduced calcification significantly (P < 0.0001). Similarly, VICs calcification strongly increased with a P2Y2 siRNA. Treatment of VICs with the calcifying medium increased the transcripts of Runx2, osteocalcin and osteonectin, whereas the addition of ARL67156 or 2-thioUTP prevented this response. In isolated VICs, LY294002, a PI3K inhibitor, significantly increased the calcification of VICs and antagonized the protective effect of P2Y2 agonist. Tunel staining showed reduced apoptotic cells with ARL 67156 and 2-thioUTP but LY294002 negated this effect (P ANOVA<0.0001). Finally, rats treated with warfarin developed AS and a significant rise of transaortic velocity, whereas the treatment with ARL67156 prevented the appearance of a stenosis. ConclusionResults acquired in this study indicate that biodisponibility of ATP is a crucial signal for survival or death of VICs and plays an important role in AS development. Hence, present findings offer novel therapeutic opportunities for the treatment of CAVD. Results acquired in this study indicate that biodisponibility of ATP is a crucial signal for survival or death of VICs and plays an important role in AS development. Hence, present findings offer novel therapeutic opportunities for the treatment of CAVD." @default.
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• W2043719962 title "483 Extracellular ATP prevents aortic valve mineralization by P2Y2 activation and PI3K/AKT survival pathway" @default.
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