Dicarbonyl stress in the absence of hyperglycemia increases endothelial inflammation and atherogenesis similar to that observed in diabetes.
- Chris Tikellis, BSc (Hons), PhD1,2,
- Raelene J Pickering, BSc (Hons), PhD1,
- Despina Tsorotes, BSc (Hons)1,
- Olivier Huet, MD, PhD1,3,
- Mark E Cooper, MB BS, PhD, FRACP1,4,
- Karin Jandeleit-Dahm, MB BS, PhD, FRACP1,4 and
- Merlin C Thomas, MBChB, PhD, FRACP1,5⇑
- 1Baker IDI Heart & Diabetes Institute, Melbourne, AUSTRALIA
- 2 Monash University, Central Clinical School, Clinical Hematology, Melbourne, AUSTRALIA
- 3 Intensive Care Unit, The Alfred Hospital, Melbourne, AUSTRALIA
- 4 Monash University, Dept. of Medicine, Melbourne, AUSTRALIA
- 5 Monash University, Dept. of Epidemiology and Preventive Medicine, Melbourne, AUSTRALIA
- Corresponding Author: Merlin C Thomas, E-mail:
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. In this paper we demonstrate that increasing plasma methylglyoxal 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 bromobenzyl-glutathione cyclopentyl diester (BBGC) 50mg/kg IP every second day) was able to increase vascular adhesion and augment atherogenesis in euglycaemic apoE knockout mice to a similar magnitude to that observed in hyperglycaemic mice with diabetes. The effects of methylglyoxal 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 as the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.
- Received June 13, 2013.
- Accepted April 28, 2014.
- © 2014 by the American Diabetes Association.
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