Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway.

Abstract

Oxidized lipoproteins may be important in the pathogenesis of atherosclerosis. Because diabetic subjects are particularly prone to vascular disease, and glucose autoxidation and protein glycation generate reactive oxygen species, we explored the role of glucose in lipoprotein oxidation. Glucose enhanced low density lipoprotein (LDL) oxidation at concentrations seen in the diabetic state. Conjugated dienes, thiobarbituric acid reactive substances, electrophoretic mobility, and degradation by macrophages were increased when LDL was modified in the presence of glucose. In contrast, free lysine groups and fibroblast degradation were reduced. Although loss of reactive lysine groups could be due to either oxidative modification or nonenzymatic glycation of apolipoprotein B-100, inhibition of lipid peroxidation by the metal chelator, diethylenetriamine pentaacetic acid, blocked the changes in free lysines. Thus, glycation of lysine residues is unlikely to account for the alterations in macrophage and fibroblast uptake of LDL modified in the presence of glucose. Glucose-mediated enhancement of LDL oxidation was partially blocked by superoxide dismutase and nearly completely inhibited by butylated hydroxytoluene. These findings indicate that glucose enhances LDL lipid peroxidation by an oxidative pathway involving superoxide and raise the possibility that the chronic hyperglycemia of diabetes accelerates lipoprotein oxidation, thereby promoting diabetic vascular disease. (J. Clin. Invest. 1994. 94:771-778.)

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

“…The patients had an elevated BMI of 30.8±3.2 kg/m 2 ,and had evidence of both macrovascular and microvascular dysfunction endothelial dysfunction. 10 Diabetes results in numerous biochemical perturbations including hyperglycaemia, increased oxidative stress, accumulation of advanced glycation end products, 41 increased NF-κB activation, 42 and dyslipidaemia 43 all of which may attenuate NO-like activity and thus inhibit BP lowering by dietary nitrate supplementation. Furthermore every subject was on at least one medication which may affect vascular function and potentially the response to inorganic nitrate.…”

Changes in superoxide dismutase mRNA expression by streptozotocin‐induced diabetes

“…The oxidative modification of LDL cholesterol by the endothelium is thought to be an important step in the alteration of various endothelium functions (Kugiyama et al, 1990;Rajavashisth et al, 1990) and the initiation of atherosclerosis (Steinberg et al, 1984). In several in vitro models of LDL oxidation, addition of SOD has been shown to be protective (Beckman et al, 1990;Heinecke et al, 1993;Kawamura et al, 1994), suggesting a potential involvement of the superoxide radical in the process in vivo. The reduced content of SOD in the aorta should effectively enhance the direct involvement of the superoxide radical in LDL oxidation.…”

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

“…those from glycation) and oxidation of free glucose and its products. Each mechanism can generate free radicals that can modify LDL, and hence potentially play a role in the enhanced cellular uptake of modified LDL [12,[14][15][16].…”