Elevated AGE-modified ApoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relationship to tissue AGEs.:relationship to tissue AGEs

BACKGROUND: Advanced glycation endproducts (AGEs) are implicated in the pathogenesis of atherosclerotic vascular disease of diabetic and nondiabetic etiology. Recent research suggests that advanced glycation of ApoB contributes to the development of hyperlipidemia. AGE-specific receptors, expressed on vascular endothelium and mononuclear cells, may be involved in both the clearance of, and the inflammatory responses to AGEs. The aim of this study was to examine whether there is a relationship between serum AGE-ApoB and AGEs in arterial tissue of older normolipidemic nondiabetic patients with occlusive atherosclerotic disease, compared with age-matched and younger asymptomatic persons.

MATERIALS AND METHODS: Serum AGE-ApoB was measured by ELISA in 21 cardiac bypass patients. Furthermore, an AGE-specific monoclonal antibody, and polyclonal antibodies against anti-AGE-receptor (anti-AGE-R) 1 and 2 were used to explore the localization and distribution of AGEs and AGE-R immunoreactivity (IR) in arterial segments excised from these patients.

RESULTS: Serum AGE-ApoB levels were significantly elevated in the asymptomatic, older population, compared with those in young healthy persons (259 +/- 24 versus 180 +/- 21 AGE U/mg of ApoB, p < 0.01). Higher AGE-ApoB levels were observed in those patients with atherosclerosis (329 +/- 23 versus 259 +/- 24 AGE U/mg ApoB, p < 0.05). Comparisons of tissue AGE-collagen with serum AGE-ApoB levels showed a significant correlation (r = 0.707, p < 0.01). In early lesions, AGE-IR occurred mostly extracellularly. In fatty streaks and dense, cellular atheromatous lesions, AGE-IR was visible within lipid-containing smooth muscle cells and macrophages, while in late-stage, acellular plaques, AGE-IR occurred mostly extracellularly. AGE-R1 and -R2 were observed on vascular endothelial and smooth-muscle cells and on infiltrating mononuclear cells in the early-stage lesions, whereas in dense, late-stage plaques, they colocalized mostly with lipid-laden macrophages. On tissue sections, scoring of AGE-immunofluorescence correlated with tissue AGE and plasma AGE-ApoB.

CONCLUSIONS: (1) The correlation between arterial tissue AGEs and circulating AGE-ApoB suggests a causal link between AGE modification of lipoproteins and atherosclerosis. AGE-specific receptors may contribute to this process. (2) Serum AGE-ApoB may serve to predict atherosclerosis in asymptomatic patients.

Lipoprotein glycation and its metabolic consequences

In people with diabetes, glycation of apolipoproteins correlates with other indices of recent glycemic control, including HbA1. For several reasons, increased glycation of apolipoproteins may play a role in the accelerated development of atherosclerosis in diabetic patients. Recognition of glycated LDL by the classical LDL receptor is impaired, whereas its uptake by human monocyte-macrophages is enhanced. These alterations may contribute to hyperlipidemia and accelerated foam-cell formation, respectively. Glycation of LDL also enhances its capacity to stimulate platelet aggregation. The uptake of VLDL from diabetic patients by human monocyte-macrophages is enhanced. This enhancement may be due, at least in part, to increased glycation of its lipoproteins. Glycation of HDL impairs its recognition by cells and reduces its effectiveness in reverse cholesterol transport. Glycation of apolipoproteins may also generate free radicals, increasing oxidative damage to the apolipoproteins themselves, the lipids in the particle core, and any neighboring macromolecules. This effect may be most significant in extravasated lipoproteins. In these, increased glycation promotes covalent binding to vascular structural proteins, and oxidative reactions may cause direct damage to the vessel wall. Glycoxidation, or browning, of sequestered lipoproteins may further enhance their atherogenicity. Finally, glycated or glycoxidized lipoproteins may be immunogenic, and lipoprotein-immune complexes are potent stimulators of foam-cell formation.

Strawberry as a functional food:an evidence-based review

Emerging research provides substantial evidence to classify strawberries as a functional food with several preventive and therapeutic health benefits. Strawberries, a rich source of phytochemicals (ellagic acid, anthocyanins, quercetin, and catechin) and vitamins (ascorbic acid and folic acid), have been highly ranked among dietary sources of polyphenols and antioxidant capacity. It should however be noted that these bioactive factors can be significantly affected by differences in strawberry cultivars, agricultural practices, storage, and processing methods: freezing versus dry heat has been associated with maximum retention of strawberry bioactives in several studies. Nutritional epidemiology shows inverse association between strawberry consumption and incidence of hypertension or serum C-reactive protein; controlled feeding studies have identified the ability of strawberries to attenuate high-fat diet induced postprandial oxidative stress and inflammation, or postprandial hyperglycemia, or hyperlipidemia in subjects with cardiovascular risk factors. Mechanistic studies have elucidated specific biochemical pathways that might confer these protective effects of strawberries: upregulation of endothelial nitric oxide synthase (eNOS) activity, downregulation of NF-kB activity and subsequent inflammation, or inhibitions of carbohydrate digestive enzymes. These health effects may be attributed to the synergistic effects of nutrients and phytochemicals in strawberries. Further studies are needed to define the optimal dose and duration of strawberry intake in affecting levels of biomarkers or pathways related to chronic diseases.