Background. Methylglyoxal (MG) and MG-glycated proteins have been described to be highly elevated in metabolic syndrome and diabetes. Although, MG is mainly detoxified by glyoxalase system to produce D-Lactate, there are other alternative pathways of MG detoxification including aldo-keto reductase (AKR) and aldehyde dehydrogenase (ALDH).

Results. In this study we investigated the role of glyoxalase I (Glo I), a key enzyme in MG detoxification, in metabolic reprogramming in experimental cardiac dysfunction. Here we showed increased level of MG-glycated proteins in myocardial samples obtained from patients with end-stage of heart failure. To evaluate the metabolic consequence of increased MG in heart failure, we utilized Glo1 transgenic mice and identified that under pathological pressure overload, mice lacking Glo1 (KO) are protected from cardiac dysfunction as compared to wild type littermate. By analyzing of MG-derived metabolites, we could detect significant increase of hydroxyacetone/acetol (the simplest ketone) and Lactaldehyde in the heart tissues obtained from Glo1-ko mice compared to wild type littermates. Accordingly, upregulation of Akr1b3, an enzyme responsible for conversion of MG to acetol in AKR pathway, was detected in Glo1-ko mice compared to wildtype littermates.

Conclusion. Taken together, our data point towards a concept, by which activation of AKR pathway as a compensatory mechanism of MG detoxification might protect the heart from failure through ketogenesis. A better understanding of this pathway in the heart, may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.