High levels of glucose can also damage extracellularly and increase the production of advanced glycosylation end-products (AGEs) in the circulation and on matrix proteins.
The AGEs directly affect cell function, arterial wall stiffness or gene expression of interacting cells. They are ligands for a number of scavenger receptors and the receptor for AGEs (RAGE). As reviewed by Goldberg and Dansky (2006), two lines
of evidence strongly support the theory that AGEs mediate diabetic complications:
-infusions of soluble RAGE, which is presumed to complex AGEs, reduce and stabilise atherosclerotic lesions, and inhibition of AGE formation reduces lesions; and diets enriched in AGEs promote lesions. Beyond AGEs, other mechanisms also link hyperglycaemia to oxidative stress and vascular dysfunction, as well as adverse effects on vascular smooth-muscle cells (Sundell, 2005) (Figure above).
-Finally, hyperglycaemia, at least at the experimental level, has also been shown to induce MMP expression in both endothelial cells and macrophages (Sundell, 2005).
As discussed above, such changes are likely to render the plaque less stable and more susceptible to rupture and hence luminal thrombosis.
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