title: 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.
abstract: 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.
  
  
  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-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.
  
  
  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.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Melpomeni
authors.initials: M
authors.lastname: Peppa
authors.forename: Changyong
authors.initials: C
authors.lastname: Lu
authors.forename: Jaime
authors.initials: J
authors.lastname: Uribarri
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000284:Administration, Oral; D000975:Antioxidants / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000517:prevention & control; D048909:Diabetes Complications / Q000517:prevention & control; D003920:Diabetes Mellitus / Q000097:blood / Q000178:diet therapy / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D015533:Transcriptional Activation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D000111:Acetylcysteine