title: Dicarbonyl stress in the absence of hyperglycemia increases endothelial inflammation and atherogenesis similar to that observed in diabetes.
abstract: 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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Central Clinical School, Clinical Hematology, Monash University, Melbourne, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Tikellis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Raelene J
authors.initials: RJ
authors.lastname: Pickering
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Despina
authors.initials: D
authors.lastname: Tsorotes
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Intensive Care Unit, The Alfred Hospital, Melbourne, Australia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Huet
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia merlin.thomas@bakeridi.edu.au.
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006943:Hyperglycemia / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D011765:Pyruvaldehyde / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D017127:Glycation End Products, Advanced; D011765:Pyruvaldehyde