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.
Highlights
Calcific aortic valve disease (CAVD) is a progressive disorder that is characterized by a fibrotic thickening of the valve leaflets and remodeling of the extracellular matrix (ECM), as well as calcium accumulation in the valvular tissue [1]
Pathological changes in AV tissue after ex vivo culture are associated with activation
Pathological of changes inthus, AV tissue after ex vivo of culture are associated with activation and differentiation
Summary
Calcific aortic valve disease (CAVD) is a progressive disorder that is characterized by a fibrotic thickening of the valve leaflets and remodeling of the extracellular matrix (ECM), as well as calcium accumulation in the valvular tissue [1]. These morphological alterations result in an immobilization of the leaflets that further results in regurgitation or stenosis of the aortic valve (AV). During this process, valvular interstitial cells (VIC), which is the main cell type of AV, are activated and display morphological and molecular changes [2]. T2D shows a steadily growing prevalence in industrialized countries and even more in middle-income and low-income countries, with considerable socio-economic consequences for health care systems [9,10,11]
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