Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

被引:79
作者
Tikellis, Chris [1 ,2 ]
Pickering, Raelene J. [1 ]
Tsorotes, Despina [1 ]
Huet, Olivier [1 ,3 ]
Cooper, Mark E. [1 ,4 ]
Jandeleit-Dahm, Karin [1 ,4 ]
Thomas, Merlin C. [1 ,5 ]
机构
[1] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia
[2] Monash Univ, Cent Clin Sch, Melbourne, Vic 3004, Australia
[3] Alfred Hosp, Intens Care Unit, Melbourne, Vic, Australia
[4] Monash Univ, Dept Med, Melbourne, Vic 3004, Australia
[5] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia
基金
英国医学研究理事会;
关键词
ADVANCED GLYCATION ENDPRODUCTS; FRUCTOSE CORN SYRUP; E-DEFICIENT MICE; END-PRODUCTS; ACCELERATED ATHEROSCLEROSIS; GLYOXALASE; METHYLGLYOXAL; RAGE; RECEPTOR; AGES;
D O I
10.2337/db13-0932
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.
引用
收藏
页码:3915 / 3925
页数:11
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