Published Online
on July 12, 2004

A more recent version of this article appeared on July 20, 2004

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Submitted on February 12, 2003
Revised on March 30, 2004
Accepted on April 9, 2004

High Levels of Dietary Advanced Glycation End Products Transform Low-Dersity 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, and 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.

^* To whom correspondence should be addressed. E-mail: helen.vlassara{at}mssm.edu.

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

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