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.
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.
Cai
Weijing
W
Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
He
John Cijiang
JC
Zhu
Li
L
Peppa
Melpomeni
M
Lu
Changyong
C
Uribarri
Jaime
J
Vlassara
Helen
H
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
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