Abstract
Background: Diabetes mellitus is a disease that is characterized by a high blood glucose concentration, which leads to advanced glycation end product (AGE) formation. AGEs have various effects on the vasculature and this may be dependent on the extent and reversibility of glycation. AGEs present in the vasculature can promote cardiovascular diseases through modifications to circulating proteins and endothelial cells. Furthermore, cardiovascular diseases are characterized by altered shear stress, including both high magnitude short duration shear and low oscillatory shear. However, the combined role of high magnitude shear stress and the presence of AGEs on endothelial cell functions have not been elucidated. Our objective was to evaluate changes to endothelial cell responses under these conditions. Methods: To accomplish this, albumin was glycated for up to 8 weeks and endothelial cells were subjected to glycated albumin for up to 5 days. Endothelial cells were then exposed to shear stress in a cone-and-plate shearing device. Endothelial cell metabolic activity, surface expression of intracellular adhesion molecule-1, thrombomodulin, tissue factor, connexin-43, and caveolin-1, cytoskeletal organization and morphology were investigated. Results: In general, the combination of pathological shear stress and irreversibly glycated albumin deteriorated endothelial cell culture conditions and cytoskeletal organization, while enhancing pro-inflammatory and pro-thrombotic markers. The expression of connexin-43 and caveolin-1, was independent of shear stress, but was markedly enhanced after exposure to irreversibly glycated albumin. Conclusions: Our data suggests that the presence of irreversible glycated albumin diminishes endothelial cell culture conditions and that this is exacerbated by the application of high magnitude shear stress. It is therefore possible that the combination of altered shear stress and glycated albumin may accelerate the pathologies seen during diabetes mellitus to promote cardiovascular diseases.
Highlights
It is well known that a diabetic vasculature differs from a normal vasculature and it promotes cardiovascular disease progression through the actions of advanced glycation end products (AGEs) on endothelial cells and platelets [1,2,3,4,5]
All data points were normalized to the cells with no added albumin exposed to the same shear stress and grown for the same duration
Human umbilical vein endothelial cells (HUVECs) metabolic activity was quantified as a means to determine the culture conditions of cells after incubation with various glycated albumin samples and exposure to varying levels of shear stress (Figure 2)
Summary
It is well known that a diabetic vasculature differs from a normal vasculature and it promotes cardiovascular disease progression through the actions of advanced glycation end products (AGEs) on endothelial cells and platelets [1,2,3,4,5]. We aimed to determine the role of glycation extent on endothelial cells exposed to varying magnitudes of shear stress. Regardless of the extent of glycation, it is clear that AGEs are present during diabetes mellitus, alter cellular functions and may promote cardiovascular disease conditions. Diabetes mellitus is a disease that is characterized by a high blood glucose concentration, which leads to advanced glycation end product (AGE) formation. Cardiovascular diseases are characterized by altered shear stress, including both high magnitude short duration shear and low oscillatory shear. The combined role of high magnitude shear stress and the presence of AGEs on endothelial cell functions have not been elucidated. Our objective was to evaluate changes to endothelial cell responses under these conditions
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