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 adequatelyaccount for the greatly increased incidence of atherosclerosis associated with diabetes. One importantcontributor could be alterations in high-density lipoprotein (HDL), which normally protects againstatherosclerosis by removing excess cholesterol from macrophage foam cells.In vitro and in vivo studies demonstrate that two ABC transporters, ABCA1 and ABCG1, promote efflux ofcellular cholesterol and phospholipids from macrophages to HDL or its apolipoproteins. Thus, factorsassociated with the diabetic milieu that modify HDL and impair its ability to interact with ABCA1 and ABCG1are likely to strongly influence atherogenesis.The many biochemical abnormalities that might modify HDL include elevated levels of glucose and free fattyacids, the metabolic hallmarks of diabetes. We have shown that polyunsaturated fatty acids (PUFAs) inconcert 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 oxidizedamino acids generated by this pathway in aortic tissue from hyperglycemic nonhuman primates. Anotherpathway implicated in human atherogenesis is myeloperoxidase, a heme protein expressed by macrophagesin human vascular lesions. We recently found that levels of 3-chlorotyrosine, a specific marker for proteindamage by myeloperoxidase, are markedly elevated in HDL isolated from atherosclerotic tissue of diabetichumans. Moreover, we showed that methionine oxidation and chlorination of a single tyrosine residue inapolipoprotein A-l, the major HDL protein, impairs the ability of apoA-l to remove cellular cholesterol by theABCA1 pathway.We hypothesize that oxidative modifications of HDL impair cholesterol efflux from macrophages andare of central importance in the pathogenesis of diabetic vascular disease. Therefore, this research willdetermine whether the glucose-PUFA and myeloperoxidase pathways pathway trigger damage to HDL andpromote 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 isolatedfrom plasma and aortic tissue of control and diabetic humans. We believe it will be essential to understandthe molecular mechanisms of artery wall damage in order to develop specific therapies against thedevastating complications of diabetes.

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Wall, Valerie Z; Barnhart, Shelley; Kanter, Jenny E et al. (2018) Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome. JCI Insight 3:
Kanter, Jenny E; Kramer, Farah; Barnhart, Shelley et al. (2018) A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome. Diabetes 67:946-959
Yuan, Chujun; Hu, Jiyuan; Parathath, Saj et al. (2018) Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice. Diabetes 67:1880-1891
Rune, Ida; Rolin, Bidda; Lykkesfeldt, Jens et al. (2018) Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics. Sci Rep 8:5416
Shao, Baohai; Heinecke, Jay W (2018) Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions? Expert Rev Proteomics 15:31-40
Basu, Debapriya; Hu, Yunying; Huggins, Lesley-Ann et al. (2018) Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor. Circ Res 122:560-567
Scolaro, Bianca; Nogueira, Marina S; Paiva, Aline et al. (2018) Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine. Mol Metab 11:137-144
Fang, Xiang; Dorcely, Brenda; Ding, Xi-Ping et al. (2018) Glycemic reduction alters white blood cell counts and inflammatory gene expression in diabetes. J Diabetes Complications 32:1027-1034
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
Bornfeldt, Karin E; Kramer, Farah; Batorsky, Anna et al. (2018) A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis. Am J Pathol 188:343-352

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