Sub - A hydroxyl radicallike species See related Commentary...

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Introduction Atherosclerotic vascular disease is the leading cause of mortality in the industrialized world, and it develops at an accelerated rate among persons with diabetes melli- tus (1, 2). However, this greatly increased incidence does not result solely from traditional risk factors, such as obesity, hypertension, and hypercholesterolemia, that frequently are seen in the diabetic population (1, 2). Therefore, there could be a more direct link between diabetes and atherosclerosis. For example, it has long been known that the degree of glycemic control strong- ly affects the risk for developing many of the disorder’s long-term complications. This observation has given rise to the glucose hypothesis, which proposes that hyperglycemia mediates many of the deleterious effects of the disease. This hypothesis has gained strong sup- port from recent clinical trials demonstrating that intensive glucose-lowering therapy dramatically reduces the incidence of microvascular disease (3–5). Possible links between glucose and vascular disease include mitochondrial dysfunction (6), pseudohypox- ia (7, 8), altered growth factor and cytokine secretion (9, 10), production of advanced glycation end products (AGE products) (11, 12), and increased protein kinase C activity (13). Another important mechanism may involve oxidative stress because a wealth of evidence implicates oxidation of LDL, the major carrier of blood cholesterol, in the pathogenesis of atherosclerosis (14–16). Indeed, glucose promotes protein glycation and AGE product formation in vitro, and AGE prod- ucts accumulate in tissues of diabetic humans and ani- mals. They also are formed by oxidative reactions in vitro, leading to the proposal that diabetes increases oxidative stress (11, 12, 17–25). Recent studies have cast doubt on the concept of a generalized increase in oxidative stress in diabetes, how- ever. For example, Wells-Knecht et al. (26) quantified levels of two oxidized amino acids, ortho- tyrosine and methionine sulfoxide, in collagen isolated from dia- betic and nondiabetic subjects. Collagen was chosen for the study because it is an extracellular protein whose slow turnover rate makes it an excellent vehicle for exploring long-term oxidative stress. In vitro studies confirmed that glycoxidation reactions generate the two abnormal amino acids in human collagen, and mass spectrometric analysis of tissue collagen showed The Journal of Clinical Investigation | April 2001 | Volume 107 | Number 7 853 A hydroxyl radical–like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease Subramaniam Pennathur, 1 Janice D. Wagner, 2 Christiaan Leeuwenburgh, 1 Kenneth N. Litwak, 2 and Jay W. Heinecke 1,3 1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA 2 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA 3 Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA Address correspondence to: Jay W. Heinecke, Division of Atherosclerosis, Nutrition and Lipid Research, Box 8046,
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Sub - A hydroxyl radicallike species See related Commentary...

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