Aortic valve disease in diabetes: Molecular mechanisms and novel therapies

Figures

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  FIGURE 1. Electron micrograph depicting a fragment of a bicuspid valve (hamster). Valvular endothelial cells (VEC) with thick and thin segments line the ventricular side of the valve. Within the rich extracellular matrix, a valvular interstitial cell (VIC) lacking a basal lamina, exhibits numerous extensions that establish focal close apposition with VECs (arrowhead) and with neighboring VIC (arrows). x13,500. By permission from Circulation Research, 59, 3, 1986, p.13, Figure 2

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  FIGURE 2. Early‐stage ultrastructural modifications of the aortic valve lesion occurred in a hyperlipemic/diabetic hamsters. Under a continuous endothelium (E) having thin areas intercalated within zones in which the cell is highly enriched in biosynthetic organelles, there is a characteristic hyperplasic, multilayered basal lamina (BL). The proliferated matrix contains numerous calcification cores (arrow). A plasma monocyte (M) insinuates a pseudopod between two valvular endothelial cells. (AL), aortic lumen. x7000. By permission from American Journal of Pathology, 148, 3, 1996, p. 1004, Figure 8

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  FIGURE 3. Ultrastructure of a lesion of the aortic valve in experimental hyperglycemia/hyperlipemia (4 weeks). The pathology progresses rapidly and the alterations include thickened VECs rich in organelles, microfilaments (MF), cytoplasmic lipid inclusions (LI), a multilayered basal lamina (BL) and the presence of valvular interstitial cell (VIC)‐ containing numerous lipid inclusions. X 24,000. By permission from American Journal of Pathology, 148, 3, 1996, p.1005, Figure 9

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  FIGURE 4. Diagram portraying diabetes‐induced accelerated progression of aortic valve atherosclerotic lesion. A. In normal conditions, valvular endothelial cells (VEC) and valvular interstitial cells (VIC) are quiescent ensuring valve homeostasis. B. The early lesion is characterized by the activation of normal VECs and the shift to a pro‐inflammatory phenotype (aVEC), the expression of new cell adhesion molecules (CAM) and subsequent monocyte (M) adhesion. VICs switch from the quiescent phenotype (qVIC) to an activated, myofibroblastic phenotype (aVIC) and an osteoblastic phenotype (oVIC). Moreover, calcification centers develop in the valvular stroma (CC). These alterations determine the onset of valvular dysfunction. C. With lesion progression, monocyte adhere and transmigrate through chronically inflamed VECs and switch to activated macrophages (MAC). Sometimes VECs undergo endothelial‐to‐mesenchymal transition (EndMT). There is an increased number of aVICs and oVICs and MAC in the valvular stroma. Chronic fibrosis develops and additional calcification centers appear, ultimately affecting valvular function

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  FIGURE 5. Diagram illustrating the high glucose (HG)‐induced progresive changes (at 7 and 14 days) of the expression of molecules in human VECs and VICs, as detected by an original 3D construct populated with valvular cells. At 7 days, the gene expression of von Willebrand factor (vWF), cytokines, cell adhesion molecules, integrins chains, laminin, pro‐osteogenic molecules: bone morphogenetic protein −2(BMP‐2), bone morphogenetic protein‐4 (BMP‐4) and RUNT‐related transcription factor 2 (RUNX2) is increased. SMAD2/3 and protein kinase K (PCK) proteins are activated. In VIC, note the enhanced expression of different cytokines, integrins, osteogenic molecules, and of RUNX2, matrix metalloproteinase 13 (MMP13) and laminin (LAM). HG activates SMAD1/5/8 and SMAD2/3 proteins and increases reactive oxygen species (ROS). Moreover, VEC and VIC in the 3D construct secrete in the conditioned media increased levels of transforming growth factor beta (TGF‐β) and bone morphogenetic protein‐2 (BMP‐2). At 14 days, in VEC, the gene expression of cell adhesion molecules, integrins and bone morphogenetic protein‐4 (BMP‐4) increases. Note that in VIC, HG increases the expression of numerous inflammatory…