This Article Full Text Full Text (PDF) All Versions of this Article: 110/3/285    most recent 01.CIR.0000135587.92455.0Dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cai, W. Articles by Vlassara, H. Search for Related Content PubMed PubMed Citation Articles by Cai, W. Articles by Vlassara, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLCYSTEINE Medline Plus Health Information Diabetes Related Collections Risk Factors Cell signalling/signal transduction Type 1 diabetes Type 2 diabetes Lipid and lipoprotein metabolism Oxidant stress

(Circulation. 2004;110:285-291.)
© 2004 American Heart Association, Inc.

Original Articles

High Levels of Dietary Advanced Glycation End Products Transform Low-Density Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients

Weijing Cai, MD; John Cijiang He, MD; Li Zhu, MD; Melpomeni Peppa, MD; Changyong Lu, MD; Jaime Uribarri, MD; Helen Vlassara, MD

From the Division of Experimental Diabetes and Aging, Department of Geriatrics (W.C., L.Z., M.P., C.L., H.V.), and Division of Nephrology, Department of Medicine (J.C., J.U.), Mount Sinai School of Medicine, New York, NY.

Correspondence to Helen Vlassara, MD, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029. E-mail helen.vlassara{at}mssm.edu

Received February 12, 2003; de novo received December 17, 2003; revision received March 30, 2004; accepted April 9, 2004.

Background— LDL modification by endogenous advanced glycation end products (AGEs) is thought to contribute to cardiovascular disease of diabetes. It remains unclear, however, whether exogenous (diet-derived) AGEs influence glycoxidation and endothelial cell toxicity of diabetic LDL.

Methods and Results— Twenty-four diabetic subjects were randomized to either a standard diet (here called high-AGE, HAGE) or a diet 5-fold lower in AGE (LAGE diet) for 6 weeks. LDL pooled from patients on HAGE diet (Db-HAGE-LDL) was more glycated than LDL from the LAGE diet group (Db-LAGE-LDL) (192 versus 92 AGE U/mg apolipoprotein B) and more oxidized (5.7 versus 1.5 nmol malondialdehyde/mg lipoprotein). When added to human endothelial cells (ECV 304 or human umbilical vein endothelial cells), Db-HAGE-LDL promoted marked ERK1/2 phosphorylation (pERK1/2) (5.5- to 10-fold of control) in a time- and dose-dependent manner compared with Db-LAGE-LDL or native LDL. In addition, Db-HAGE-LDL stimulated NF-B activity significantly in ECV 304 and human umbilical vein endothelial cells (2.3-fold above baseline) in a manner inhibitable by a MEK inhibitor PD98059 (10 µmol/L), the antioxidant N-acetyl-L-cysteine, NAC (30 mmol/L), and the NADPH oxidase inhibitor DPI (20 µmol/L). In contrast to Db-LAGE-LD and native LDL, Db-HAGE-LDL induced significant soluble vascular cell adhesion molecule-1 production (2.3-fold), which was blocked by PD98059, NAC, and DPI.

Conclusions— Exposure to daily dietary glycoxidants enhances LDL-induced vascular toxicity via redox-sensitive mitogen-activated protein kinase activation. This can be prevented by dietary AGE restriction.

Key Words: atherosclerosis • diabetes • endothelium • glycotoxins • glycation • kinases

This article has been cited by other articles:

				T. Buetler, T. Henle, and H. Vlassara The Effects of AGEing on Diet Am. J. Pathol., January 1, 2009; 174(1): 351 - 353. [Abstract] [Full Text] [PDF]

				E. Linden, W. Cai, J. C. He, C. Xue, Z. Li, J. Winston, H. Vlassara, and J. Uribarri Endothelial Dysfunction in Patients with Chronic Kidney Disease Results from Advanced Glycation End Products (AGE)-Mediated Inhibition of Endothelial Nitric Oxide Synthase through RAGE Activation Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 691 - 698. [Abstract] [Full Text] [PDF]

				Y. Fan, Y. Wang, Z. Tang, H. Zhang, X. Qin, Y. Zhu, Y. Guan, X. Wang, B. Staels, S. Chien, et al. Suppression of Pro-inflammatory Adhesion Molecules by PPAR-{delta} in Human Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 315 - 321. [Abstract] [Full Text] [PDF]

				J. Uribarri, A. Stirban, D. Sander, W. Cai, M. Negrean, C. E. Buenting, T. Koschinsky, and H. Vlassara Single Oral Challenge by Advanced Glycation End Products Acutely Impairs Endothelial Function in Diabetic and Nondiabetic Subjects Diabetes Care, October 1, 2007; 30(10): 2579 - 2582. [Abstract] [Full Text] [PDF]

				M. Negrean, A. Stirban, B. Stratmann, T. Gawlowski, T. Horstmann, C. Gotting, K. Kleesiek, M. Mueller-Roesel, T. Koschinsky, J. Uribarri, et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus Am. J. Clinical Nutrition, May 1, 2007; 85(5): 1236 - 1243. [Abstract] [Full Text] [PDF]

				J. Uribarri, W. Cai, M. Peppa, S. Goodman, L. Ferrucci, G. Striker, and H. Vlassara Circulating Glycotoxins and Dietary Advanced Glycation Endproducts: Two Links to Inflammatory Response, Oxidative Stress, and Aging J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2007; 62(4): 427 - 433. [Abstract] [Full Text] [PDF]

				J. Uribarri and K. R. Tuttle Advanced Glycation End Products and Nephrotoxicity of High-Protein Diets Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1293 - 1299. [Abstract] [Full Text] [PDF]

				A. Goldin, J. A. Beckman, A. M. Schmidt, and M. A. Creager Advanced Glycation End Products: Sparking the Development of Diabetic Vascular Injury Circulation, August 8, 2006; 114(6): 597 - 605. [Abstract] [Full Text] [PDF]

				H. Liu, F. Zheng, Z. Li, J. Uribarri, B. Ren, R. Hutter, J. R. Tunstead, J. Badimon, G. E. Striker, and H. Vlassara Reduced Acute Vascular Injury and Atherosclerosis in Hyperlipidemic Mice Transgenic for Lysozyme Am. J. Pathol., July 1, 2006; 169(1): 303 - 313. [Abstract] [Full Text] [PDF]

				A. G. Huebschmann, J. G. Regensteiner, H. Vlassara, and J. E.B. Reusch Diabetes and Advanced Glycoxidation End Products. Diabetes Care, June 1, 2006; 29(6): 1420 - 1432. [Full Text] [PDF]

				T. P. Remus, A. V. Zima, J. Bossuyt, D. J. Bare, J. L. Martin, L. A. Blatter, D. M. Bers, and G. A. Mignery Biosensors to Measure Inositol 1,4,5-Trisphosphate Concentration in Living Cells with Spatiotemporal Resolution J. Biol. Chem., January 6, 2006; 281(1): 608 - 616. [Abstract] [Full Text] [PDF]

				J. M. Bohlender, S. Franke, G. Stein, and G. Wolf Advanced glycation end products and the kidney Am J Physiol Renal Physiol, October 1, 2005; 289(4): F645 - F659. [Abstract] [Full Text] [PDF]

				G. Basta, G. Lazzerini, S. Del Turco, G. M. Ratto, A. M. Schmidt, and R. De Caterina At Least 2 Distinct Pathways Generating Reactive Oxygen Species Mediate Vascular Cell Adhesion Molecule-1 Induction by Advanced Glycation End Products Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1401 - 1407. [Abstract] [Full Text] [PDF]

				D. J. Bare, C. S. Kettlun, M. Liang, D. M. Bers, and G. A. Mignery Cardiac Type 2 Inositol 1,4,5-Trisphosphate Receptor: INTERACTION AND MODULATION BY CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II J. Biol. Chem., April 22, 2005; 280(16): 15912 - 15920. [Abstract] [Full Text] [PDF]