Autor:innen:
T. Fleming (Heidelberg, DE)
B. von Nettelbladt (Heidelberg, DE)
J. Morgenstern (Heidelberg, DE)
M. Campos (Heidelberg, DE)
M. Le Marois (Heidelberg, DE)
M. Bartosova (Heidelberg, DE)
I. Hausser (Heidelberg, DE)
C. Schwab (Heidelberg, DE)
A. Fischer (Heidelberg, DE)
P. Nawroth (Heidelberg, DE)
J. Szendrödi (Heidelberg, DE)
S. Herzig (Neuherberg, DE)
Introduction & Open Questions
Elevated levels of methylglyoxal (MG) have been reported to be associated with progression and development of numerous pathological conditions, of which diabetes is the most predominant. It still remains unclear, despite extensive studies, what the cellular effects of MG are and how they are induced within the intracellular environment.
Methods:
The pharmokinetics of MG, its detoxification via the glyoxalase system, and the formation of MG-H1, a major post-translational modification induced by MG, was studied in murine cardiac endothelial using immunoassay and liquid chromatography, tandem mass spectrometry. Cells were stimulated with increasing concentrations of exogenous MG and the effects on cell viability markers, proliferation, metabolism and endothelial phenotype assessed.
Results:
It was found that when the intracellular concentration of MG was transiently increased 10-fold relative to the basal levels, an equivalent increase in MG-H1 was observed, and was associated with an accumulation of the modification in the nucleus. MG induces a dose-dependent inhibition of energy metabolism, synthesis of macromolecules and ultimately proliferation. This inhibition was not associated with the induction of cell death, DNA damage or quiescence or senescence. The resulting cellular phenotype, referred to as cellular stunning, could be characterized as a non-proliferating state, associated with the induction of endothelial dysfunction.
Conclusions:
MG-induced cellular stunning describes a new hallmark for cellular dysfunction which could lead to alterations in tissue homeostasis as well as cell-to-cell interactions, thereby contributing to the pathogenesis of late diabetic complications, such as cardiovascular disease.