Glycation of LDL under hyperglycemic conditions is likely to result in increased formation of oxidized LDL (154). Several mechanisms have been proposed to explain the increased oxidation of lipoproteins in diabetes. One of them involves the auto-oxidation of simple monosaccharides (155,156), such as glucose, and of fructose-lysine
(155,156,157), the first Amadori rearrangement product, under physiological conditions and in the presence of trace amounts of metal ions. Auto-oxidation of these compounds generates superoxide radicals and lipid peroxidation occurs. Another mechanism possibly responsible for increased oxidation of LDL in diabetes is the impaired clearance of glycated LDL that leads to an increase in the lipoprotein circulation time and facilitates its exposure to oxidative stress. In damaged vessel walls, trapping of LDL as a result of covalent glucose-derived crosslinking of LDL to glycated structural proteins may be yet another mechanism contributing to increased LDL oxidation in diabetes.
Several studies support the above mechanisms. Brownlee and associates (158) have reported an increase in LDL-collagen crosslinking when the lipoprotein is exposed to modified collagen (containing browning products), compared to control collagen. Some studies have shown that glycated LDL is more susceptible to oxidation than nonglycated LDL and that increased oxidative modification of LDL occurs in presence of high glucose levels (155,157). Tsai and associates (159) showed that in poorly controlled IDDM patients without macrovascular disease, the lag phase of conjugated diene formation after initiation of LDL oxidation by the addition of copper was shorter than in normal control subjects. That increase in susceptibility to oxidation was not associated with an increase of small dense LDL in the diabetic population, but with a decrease in the total peroxyl radical trapping potential of plasma (TRAP) which was significantly decreased in the IDDM patients. The decrease in TRAP was secondary to a decrease in uric acid and vitamin A. Data from our own laboratory shows that, in contrast to what happens in poorly controlled diabetics, in IDDM without pre-existent complications and with normal lipid levels and good glycemic control, the susceptibility of LDL to oxidation is not enhanced (160).
That oxidized or glyco-oxidized LDL indeed play an important role in the pathogen-esis of atherosclerosis has been confirmed by several lines of evidence: the presence of oxidized lipoproteins in the vessel wall (161,162), as demonstrated by immunochemical staining of lesions with antibodies recognizing oxidation-specific epitopes, and the demonstration that regression of lesions may occur in animals treated with antioxidants (163). Recently, AGE epitopes have also been described in atherosclerotic lesions of euglycemic rabbits (164). Interestingly, the AGE epitopes were found in similar locations as the epitopes generated during the modification of lipoproteins by oxidation. Other studies show that blockade of RAGE results in decreased inflammation in preformed lesions in streptozotocin diabetic apo-E-deficient mice (165). Because RAGE binds to a large number of ligands, in addition to AGEs, it is not known if the effects of RAGE blockade in this study were as a result of decreased uptake of AGEs. In fact, RAGE blockade reduced atherosclerotic lesion size (165) and intimal thickening after arterial injury (166) in nondiabetic mice, suggesting that the role for RAGE ligands is not dependent on the diabetic state.
Several clinical studies further strengthened the morphological findings described above. Regnstrom and associates (167) have shown that the degree of susceptibility to oxidation of LDL isolated from 35 male survivors of MI was positively correlated with the severity of coronary atherosclerosis. Several other investigators described increased oxidizability of LDL in patients with coronary heart disease (168), and patients with carotid or femoral atherosclerosis (169).
In contrast with the pletora of information that exists concerning LDL oxidation very little is known concerning oxidation of other lipoproteins. Oxidation of VLDL has been shown to be cytotoxic (170) but very little is known concerning possible metabolic alterations that may result from the oxidation of this lipoprotein. Oxidative modification of HDL in vitro has been shown to remove the ability of HDL to stimulate cholesterol efflux from foam cells (171). Recently, Bowry and associates (172) reported that HDL is the major carrier of oxidized lipids in plasma and may be responsible for the hepatic clearance of oxidized lipids from plasma.
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