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