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Article

Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling

by
Jessica I. Selig
1,
Joana Boulgaropoulos
1,
Naima Niazy
1,
D. Margriet Ouwens
2,3,4,
Karlheinz Preuß
5,
Patrick Horn
6,
Ralf Westenfeld
6,
Artur Lichtenberg
1,
Payam Akhyari
1,* and
Mareike Barth
1
1
Department of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany
2
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Auf’m Hennekamp 65, 40225 Düsseldorf, Germany
3
German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, Neuherberg, 85764 München, Germany
4
Department of Endocrinology, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium
5
Faculty of Biotechnology, Bioprocessing, Modulation and Simulation, University of Applied Sciences Mannheim, Paul-Wittsack-Straße 10, 68163 Mannheim, Germany
6
Department of Cardiology, Pneumology and Angiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(13), 6976; https://doi.org/10.3390/ijms22136976
Submission received: 10 May 2021 / Revised: 17 June 2021 / Accepted: 23 June 2021 / Published: 28 June 2021
(This article belongs to the Special Issue Molecular Mechanisms of Aortic Valve Disease)
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Abstract

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.
Keywords: aortic valve stenosis; calcific aortic valve disease; fibrosis; diabetes mellitus; hyperinsulinemia; hyperglycemia; insulin signaling; 3D tissue culture; bioreactor; static tissue culture aortic valve stenosis; calcific aortic valve disease; fibrosis; diabetes mellitus; hyperinsulinemia; hyperglycemia; insulin signaling; 3D tissue culture; bioreactor; static tissue culture

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MDPI and ACS Style

Selig, J.I.; Boulgaropoulos, J.; Niazy, N.; Ouwens, D.M.; Preuß, K.; Horn, P.; Westenfeld, R.; Lichtenberg, A.; Akhyari, P.; Barth, M. Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling. Int. J. Mol. Sci. 2021, 22, 6976. https://doi.org/10.3390/ijms22136976

AMA Style

Selig JI, Boulgaropoulos J, Niazy N, Ouwens DM, Preuß K, Horn P, Westenfeld R, Lichtenberg A, Akhyari P, Barth M. Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling. International Journal of Molecular Sciences. 2021; 22(13):6976. https://doi.org/10.3390/ijms22136976

Chicago/Turabian Style

Selig, Jessica I., Joana Boulgaropoulos, Naima Niazy, D. Margriet Ouwens, Karlheinz Preuß, Patrick Horn, Ralf Westenfeld, Artur Lichtenberg, Payam Akhyari, and Mareike Barth. 2021. "Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling" International Journal of Molecular Sciences 22, no. 13: 6976. https://doi.org/10.3390/ijms22136976

APA Style

Selig, J. I., Boulgaropoulos, J., Niazy, N., Ouwens, D. M., Preuß, K., Horn, P., Westenfeld, R., Lichtenberg, A., Akhyari, P., & Barth, M. (2021). Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling. International Journal of Molecular Sciences, 22(13), 6976. https://doi.org/10.3390/ijms22136976

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