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

• Published in: Circulation (New York, N.Y.) Vol. 110; no. 3; p. 285
• Main Authors: Cai, Weijing, He, John Cijiang, Zhu, Li, Peppa, Melpomeni, Lu, Changyong, Uribarri, Jaime, Vlassara, Helen
• Format: Journal Article
• Language: English
• Published: United States 20.07.2004
• Subjects: Acetylcysteine - pharmacology; Administration, Oral; Antioxidants - pharmacology; Cardiovascular Diseases - prevention & control; Diabetes Complications - prevention & control; Diabetes Mellitus - blood; Diabetes Mellitus - diet therapy; Diabetes Mellitus - enzymology; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - metabolism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Glycation End Products, Advanced - administration & dosage; Glycation End Products, Advanced - pharmacology; Humans; Lipoproteins, LDL - blood; Lipoproteins, LDL - chemistry; Lipoproteins, LDL - toxicity; Male; Middle Aged; NADPH Oxidases - antagonists & inhibitors; NF-kappa B - metabolism; Oxidation-Reduction; Transcriptional Activation; Vascular Cell Adhesion Molecule-1 - biosynthesis
• ISSN: 1524-4539
• DOI: 10.1161/01.CIR.0000135587.92455.0D

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. 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-kappaB 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 micromol/L), the antioxidant N-acetyl-l-cysteine, NAC (30 mmol/L), and the NADPH oxidase inhibitor DPI (20 micromol/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. 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.