{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:16:08Z","timestamp":1784715368510,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["421961956"],"award-info":[{"award-number":["421961956"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2D) is one of the prominent risk factors for the development and progression of calcific aortic valve disease. Nevertheless, little is known about molecular mechanisms of how T2D affects aortic valve (AV) remodeling. In this study, the influence of hyperinsulinemia and hyperglycemia on degenerative processes in valvular tissue is analyzed in intact AV exposed to an either static or dynamic 3D environment, respectively. The complex native dynamic environment of AV is simulated using a software-governed bioreactor system with controlled pulsatile flow. Dynamic cultivation resulted in significantly stronger fibrosis in AV tissue compared to static cultivation, while hyperinsulinemia and hyperglycemia had no impact on fibrosis. The expression of key differentiation markers and proteoglycans were altered by diabetic conditions in an environment-dependent manner. Furthermore, hyperinsulinemia and hyperglycemia affect insulin-signaling pathways. Western blot analysis showed increased phosphorylation level of protein kinase B (AKT) after acute insulin stimulation, which was lost in AV under hyperinsulinemia, indicating acquired insulin resistance of the AV tissue in response to elevated insulin levels. These data underline a complex interplay of diabetic conditions on one hand and biomechanical 3D environment on the other hand that possesses an impact on AV tissue remodeling.<\/jats:p>","DOI":"10.3390\/ijms22136976","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T22:43:06Z","timestamp":1624920186000},"page":"6976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment\u2014Impact on Aortic Valve Remodeling"],"prefix":"10.3390","volume":"22","author":[{"given":"Jessica I.","family":"Selig","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Boulgaropoulos","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naima","family":"Niazy","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6709-2702","authenticated-orcid":false,"given":"D. Margriet","family":"Ouwens","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Auf\u2019m Hennekamp 65, 40225 D\u00fcsseldorf, Germany"},{"name":"German Center for Diabetes Research (DZD), Ingolst\u00e4dter Landstra\u00dfe 1, Neuherberg, 85764 M\u00fcnchen, Germany"},{"name":"Department of Endocrinology, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlheinz","family":"Preu\u00df","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology, Bioprocessing, Modulation and Simulation, University of Applied Sciences Mannheim, Paul-Wittsack-Stra\u00dfe 10, 68163 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pneumology and Angiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Westenfeld","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pneumology and Angiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Lichtenberg","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6452-8678","authenticated-orcid":false,"given":"Payam","family":"Akhyari","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, Moorenstra\u00dfe 5, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.15420\/ecr.2015.10.2.108","article-title":"Calcific Aortic Valve Disease: Molecular Mechanisms And Therapeutic Approaches","volume":"10","author":"Lerman","year":"2015","journal-title":"Eur. 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