Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Dicarbonyl stress in the absence of hyperglycaemia increases endothelial inflammation and atherogenesis similar to that observed in diabetes. (#224)

Raelene Pickering 1 , Chris Tikellis 1 , Merlin Thomas 1
  1. Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
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. Increasing plasma methylglyoxal to levels observed in diabetic mice with exogenous methylglyoxal (1% in drinking water) increases vascular adhesion and inflammation, and augments 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 methylglyoxal exposure, although it was not normalised. Independent of RAGE-signaling, dicarbonyls also lead to the induction of mitochondrial oxidative stress, which when attenuated by the peroxynitrite scavenger, MnTBAP led to complete abrogation of the endothelial effects of methylglyoxal. Taken together, these data suggest the presence of two key pathways for dicarbonyl mediated dysfunction, the first (dominant) pathway mediated via RAGE signalling, and the second via the (RAGE-independent) induction of mitochondrial ROS. Consequently, combination approaches will be essential to attenuate the effects of dicarbonyls in the vasculature and prevent diabetic vascular complications