Methylglyoxal-Glyoxalase 1 Balance: The Root of Vascular Damage

Cecilia Nigro,Francesco Beguinot,Alessia Leone,Claudia Miele,Pietro Formisano,Michele Longo,Paola Mirra,Gregory Raciti

doi:10.3390/ijms18010188

Abstract

The highly reactive dicarbonyl methylglyoxal (MGO) is mainly formed as byproduct of glycolysis. Therefore, high blood glucose levels determine increased MGO accumulation. Nonetheless, MGO levels are also increased as consequence of the ineffective action of its main detoxification pathway, the glyoxalase system, of which glyoxalase 1 (Glo1) is the rate-limiting enzyme. Indeed, a physiological decrease of Glo1 transcription and activity occurs not only in chronic hyperglycaemia but also with ageing, during which MGO accumulation occurs. MGO and its advanced glycated end products (AGEs) are associated with age-related diseases including diabetes, vascular dysfunction and neurodegeneration. Endothelial dysfunction is the first step in the initiation, progression and clinical outcome of vascular complications, such as retinopathy, nephropathy, impaired wound healing and macroangiopathy. Because of these considerations, studies have been centered on understanding the molecular basis of endothelial dysfunction in diabetes, unveiling a central role of MGO-Glo1 imbalance in the onset of vascular complications. This review focuses on the current understanding of MGO accumulation and Glo1 activity in diabetes, and their contribution on the impairment of endothelial function leading to diabetes-associated vascular damage.

Highlights

Methylglyoxal (MGO) is a dicarbonyl aldehyde mainly formed as byproduct of glycolysis [1]
This situation may be further increased under conditions that lead to higher triosephosphate concentrations, like increased glucose metabolism in hyperglycaemia [5], impairment of the pentose pathway decreasing GA3P disposal, or increased anaerobic glycolysis occurring in hypoxia [6]
These findings provide further evidence that MGO is a causative factor in the pathogenesis of atherosclerosis and development of macrovascular diabetic complications

Summary

Introduction

Methylglyoxal (MGO) is a dicarbonyl aldehyde mainly formed as byproduct of glycolysis [1]. A study performed in Goto-Kakizaki diabetic rats demonstrates that endothelial dysfunction is worsened by MGO treatment, which increases oxidative stress, AGE formation and inflammation with a decline in NO bioavailability [58]. MGO accumulation in arterial walls causes vascular contractile dysfunction in spontaneously hypertensive rats [59], and Dhar et al have demonstrated that MGO treatment activates NFκB through RAGE, thereby increasing renin-angiotensin levels and blood pressure in Sprague-Dawley rats [60]. These findings provide further evidence that MGO is a causative factor in the pathogenesis of atherosclerosis and development of macrovascular diabetic complications. Further efforts in the development of pharmacological intervention to prevent dicarbonyl stress are needed to provide new therapeutic options aimed at preventing vascular dysfunction in diabetes and other age-related diseases

MGO-Induced Insulin-Resistance: A Link to Endothelial Dysfunction

Mouse Models of MGO Accumulation

Findings

Conclusions