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

被引:132
作者
Cai, WJ
He, JCJ
Zhu, L
Peppa, M
Lu, CY
Uribarri, J
Vlassara, H
机构
[1] CUNY Mt Sinai Sch Med, Dept Geriatr, Div Expt Diabet & Aging, New York, NY 10029 USA
[2] CUNY Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA
关键词
atherosclerosis; diabetes; endothelium; glycotoxins; glycation; kinases;
D O I
10.1161/01.CIR.0000135587.92455.0D
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-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 mumol/L), the antioxidant N-acetyl-L-cysteine, NAC (30 mumol/L), and the NADPH oxidase inhibitor DPI (20 mumol/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.
引用
收藏
页码:285 / 291
页数:7
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