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.

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National Heart, Lung, and Blood Institute (NHLBI)
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Krishack, Paulette A; Sontag, Timothy J; Getz, Godfrey S et al. (2016) Serum amyloid A regulates monopoiesis in hyperlipidemic Ldlr(-/-) mice. FEBS Lett 590:2650-60
Ronsein, Graziella E; Hutchins, Patrick M; Isquith, Daniel et al. (2016) Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects. Arterioscler Thromb Vasc Biol 36:404-11
Shimizu-Albergine, Masami; Van Yserloo, Brian; Golkowski, Martin G et al. (2016) SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci U S A 113:E5685-93
Bornfeldt, Karin E (2016) Does Elevated Glucose Promote Atherosclerosis? Pros and Cons. Circ Res 119:190-3
Han, Chang Yeop (2016) Roles of Reactive Oxygen Species on Insulin Resistance in Adipose Tissue. Diabetes Metab J 40:272-9
Monette, Jeffrey S; Hutchins, Patrick M; Ronsein, Graziella E et al. (2016) Patients With Coronary Endothelial Dysfunction Have Impaired Cholesterol Efflux Capacity and Reduced HDL Particle Concentration. Circ Res 119:83-90
Ronsein, Graziella E; Reyes-Soffer, Gissette; He, Yi et al. (2016) Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone. Mol Cell Proteomics 15:1083-93
Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E et al. (2016) Serum amyloid A impairs the antiinflammatory properties of HDL. J Clin Invest 126:266-81
Tang, Chongren; Liu, Yuhua; Yang, Wendy et al. (2016) Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice. J Lipid Res 57:100-8
Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J (2016) Lipid Use and Misuse by the Heart. Circ Res 118:1736-51

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