期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 13, 页码 -出版社
MDPI
DOI: 10.3390/ijms22136976
关键词
aortic valve stenosis; calcific aortic valve disease; fibrosis; diabetes mellitus; hyperinsulinemia; hyperglycemia; insulin signaling; 3D tissue culture; bioreactor; static tissue culture
资金
- German Research Foundation (DFG) [421961956]
The study analyzed the influence of hyperinsulinemia and hyperglycemia on degenerative processes in valvular tissue, and found that dynamic cultivation resulted in significantly stronger fibrosis in AV tissue compared to static cultivation. Hyperinsulinemia and hyperglycemia altered the expression of key differentiation markers and proteoglycans in a manner dependent on the environment, and affected insulin-signaling pathways.
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.
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