Impact of carbonylation on glutathione peroxidase-1 activity in human
hyperglycemic endothelial cells
#MMPMID29499564
Sultan CS
; Saackel A
; Stank A
; Fleming T
; Fedorova M
; Hoffmann R
; Wade RC
; Hecker M
; Wagner AH
Redox Biol
2018[Jun]; 16
(?): 113-122
PMID29499564
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AIMS: High levels of glucose and reactive carbonyl intermediates of its
degradation pathway such as methylglyoxal (MG) may contribute to diabetic
complications partly via increased generation of reactive oxygen species (ROS).
This study focused on glutathione peroxidase-1 (GPx1) expression and the impact
of carbonylation as an oxidative protein modification on GPx1 abundance and
activity in human umbilical vein endothelial cells (HUVEC) under conditions of
mild to moderate oxidative stress. RESULTS: High extracellular glucose and MG
enhanced intracellular ROS formation in HUVECs. Protein carbonylation was only
transiently augmented pointing to an effective antioxidant defense in these
cells. Nitric oxide synthase expression was decreased under hyperglycemic
conditions but increased upon exposure to MG, whereas superoxide dismutase
expression was not significantly affected. Increased glutathione peroxidase (GPx)
activity seemed to compensate for a decrease in GPx1 protein due to enhanced
degradation via the proteasome. Mass spectrometry analysis identified Lys-114 as
a possible carbonylation target which provides a vestibule for the substrate
H(2)O(2) and thus enhances the enzymatic reaction. INNOVATION: Oxidative protein
carbonylation has so far been associated with functional inactivation of modified
target proteins mainly contributing to aging and age-related diseases. Here, we
demonstrate that mild oxidative stress and subsequent carbonylation seem to
activate protective cellular redox signaling pathways whereas severe oxidative
stress overwhelms the cellular antioxidant defense leading to cell damage.
CONCLUSIONS: This study may contribute to a better understanding of redox
homeostasis and its role in the development of diabetes and related vascular
complications.
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