Molecular Mechanisms of Atherogenesis in Diabetes

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Both diabetic men and diabetic women are at greatly increased risk for atherosclerotic vascular disease. Although certain risk factors for atherosclerosis are frequently present in diabetics, they cannot adequately account for the greatly increased incidence of atherosclerosis associated with diabetes. One important contributor could be alterations in high-density lipoprotein (HDL), which normally protects against atherosclerosis by removing excess cholesterol from macrophage foam cells. In vitro and in vivo studies demonstrate that two ABC transporters, ABCA1 and ABCG1, promote efflux of cellular cholesterol and phospholipids from macrophages to HDL or its apolipoproteins. Thus, factors associated with the diabetic milieu that modify HDL and impair its ability to interact with ABCA1 and ABCG1 are likely to strongly influence atherogenesis. The many biochemical abnormalities that might modify HDL include elevated levels of glucose and free fatty acids, the metabolic hallmarks of diabetes. We have shown that polyunsaturated fatty acids (PUFAs) in concert with glucose or other reactive carbonyls generate an intermediate that resembles hydroxyl radical. Using a combination of gas chromatography and mass spectrometry, we detected the pattern of oxidized amino acids generated by this pathway in aortic tissue from hyperglycemic nonhuman primates. Another pathway implicated in human atherogenesis is myeloperoxidase, a heme protein expressed by macrophages in human vascular lesions. We recently found that levels of 3-chlorotyrosine, a specific marker for protein damage by myeloperoxidase, are markedly elevated in HDL isolated from atherosclerotic tissue of diabetic humans. Moreover, we showed that methionine oxidation and chlorination of a single tyrosine residue in apolipoprotein A-l, the major HDL protein, impairs the ability of apoA-l to remove cellular cholesterol by the ABCA1 pathway. We hypothesize that oxidative modifications of HDL impair cholesterol efflux from macrophages and are of central importance in the pathogenesis of diabetic vascular disease. Therefore, this research will determine whether the glucose-PUFA and myeloperoxidase pathways pathway trigger damage to HDL and promote plaque development. We will seek evidence for these pathways through complementary studies of (i) cultured human endothelial cells and monocyte/macrophages, (ii) mouse models, and (iii) HDL isolated from plasma and aortic tissue of control and diabetic humans. We believe it will be essential to understand the molecular mechanisms of artery wall damage in order to develop specific therapies against the devastating complications of diabetes.