{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:59:21Z","timestamp":1788919161202,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T00:00:00Z","timestamp":1521504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LI 1994\/1\u20101"],"award-info":[{"award-number":["LI 1994\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>\n                    Calcific aortic valve disease is an active disease process with lipoprotein deposition, chronic in\u2010flammation, and progressive leaflet degeneration. Expression of ectonucleotidases, a group of membrane\u2010bound enzymes that regulate the metabolism of ATP and its metabolites, may coregulate the degeneration process of valvular interstitial cells (VICs). The aim of this study was to investigate the role of the enzymes of the purinergic system in the degeneration process of VICs. Ovine VICs were cultivated\n                    <jats:italic>in vitro<\/jats:italic>\n                    under different prodegenerative conditions and treated with inhibitors of ectonucleoside triphosphate diphosphohydrolase 1 (CD39)\/ectonucleotide pyrophosphatase\/phosphodiesterase 1 (ENPP1), and 5\u2032\u2010nucleotidase (CD73), as well as with adenosine and adenosine receptor agonists. Experiments were performed both in 2\u2010dimensional (2\u2010D) and 3\u2010dimensional (3\u2010D) cell\u2010culture models. Our main findings were that VICs continuously release ATP. Inhibition of ATP hydrolyzing enzymes (CD39 and ENPP1) resulted in profound prodegenerative effects with a vigorous up\u2010regulation of CD39, ENPP1, and CD73, as well as TGF\u2010\u03b21 and osteopontin at the gene level. In our 3\u2010D model, the effect was more pronounced than in 2\u2010D monolayers. Increasing adenosine levels, as well as stimulating the adenosine receptors A\n                    <jats:sub>2A<\/jats:sub>\n                    and A\n                    <jats:sub>2B<\/jats:sub>\n                    , exhibited strong prodegenerative effects, whereas conversely, lowering adenosine levels by inhibition of CD73 resulted in protective effects against degeneration. Dysregulation of any one of these enzymes plays an important role in the degeneration process of VICs. Stimulation of ATP and adenosine has prodegenerative effects, whereas lowering the adenosine levels exerts a protective effect.\u2014Weber, A., Barth, M., Selig, J. I., Raschke, S., Dakaras, K., Hof, A., Hesse, J., Schrader, J., Lichtenberg, A., Akhyari, P. Enzymes of the purinergic signaling system exhibit diverse effects on the degeneration of valvular interstitial cells in a 3\u2010D microenvironment.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 32, 4356\u20134369 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201701326r","type":"journal-article","created":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T16:59:22Z","timestamp":1521565162000},"page":"4356-4369","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Enzymes of the purinergic signaling system exhibit diverse effects on the degeneration of valvular interstitial cells in a 3\u2010D microenvironment"],"prefix":"10.1096","volume":"32","author":[{"given":"Andreas","family":"Weber","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Isabel","family":"Selig","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silja","family":"Raschke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Dakaras","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hof","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hesse","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Schrader","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Lichtenberg","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Akhyari","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Department of Molecular Cardiology Medical Faculty Heinrich\u2010Heine\u2010University Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,3,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.486738"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2007.2126"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.006767"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1278283"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-016-9679-z"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-016-9695-z"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1620\/tjem.243.255","article-title":"Know me! 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