Reactive carbonyl species in health and chronic disease: from methylglyoxal to an integrative network of metabolic regulation.

The prevalence of chronic diseases is increasing dramatically, but the metabolism, particularly the pervasive carbonyl stress that accompanies many of these conditions, is rarely considered a potential cause. Reactive carbonyl species are spontaneously generated through a variety of endogenous metabolic reactions, and contain highly reactive carbonyl groups. Methylglyoxal, a prime reactive carbonyl, has been linked to cardiovascular disease, diabetes and its complications, obesity, chronic kidney disease, and ageing. Its detoxification is mainly regulated by the glyoxalase system; however, surprisingly, studies in mice, zebrafish and drosophila with a knockout of glyoxalase 1 showed viable animals with only minor metabolic phenotypes. Importantly, compensatory mechanisms for other potential methylglyoxal-detoxifying enzymes, including aldehyde dehydrogenases and aldo reductases, were identified in glyoxalase 1 knockout animals. Subsequent knockout studies of different Aldehyde-Dehydrogenases and Aldo-Keto-Reductases have demonstrated that Glyoxalase 1 does not solely regulate the metabolism of reactive carbonyl species and organ functions. Instead, other reactive carbonyl species, together with their corresponding detoxification enzymes, exhibit distinct organ susceptibility. These detoxifying enzyme systems are interconnected at multiple levels in a complex and redundant manner, and their dysregulation can lead to chronic pathological conditions. Conceptually, the review aims to focus on future cardiovascular research investigating the specificity of different reactive carbonyl species to their respective detoxification systems and the interplay and organ-specific regulation of these detoxification pathways. The future goal is to develop reactive carbonyl species profiles and markers of inadequate detoxification in order to identify new patient subgroups. Another future challenge will be to establish reactive carbonyl species profiles and corresponding enzyme system activities as biomarkers for predicting, diagnosing and monitoring chronic diseases in translational and clinical contexts. Ultimately, we suggest to develop potent and specific reactive carbonyl species scavengers, as well as detoxifying enzyme activators, and define new patient subgroups with different treatment needs and prognoses.