Abstract
Background Malondialdehyde (MDA), glyoxal (GO), and methylglyoxal (MGO) levels increase in atherosclerosis and diabetes patients. Recent reports demonstrate that GO and MGO cause vascular endothelial barrier dysfunction whereas no evidence is available for MDA. Methods To compare the effects of MDA, GO, or MGO on endothelial permeability, we used human EA.hy926 endothelial cells as a standard model. To study cortical cytoplasm motility and cytoskeletal organization in endothelial cells, we utilized time-lapse microscopy and fluorescent microscopy. To compare dicarbonyl-modified protein band profiles in these cells, we applied Western blotting with antibodies against MDA- or MGO-labelled proteins. Results MDA (150–250 μM) irreversibly suppressed the endothelial cell barrier, reduced lamellipodial activity, and prevented intercellular contact formation. The motile deficiency of MDA-challenged cells was accompanied by alterations in microtubule and microfilament organization. These detrimental effects were not observed after GO or MGO (250 μM) administration regardless of confirmed modification of cellular proteins by MGO. Conclusions Our comparative study demonstrates that MDA is more damaging to the endothelial barrier than GO or MGO. Considering that MDA endogenous levels exceed those of GO or MGO and tend to increase further during lipoperoxidation, it appears important to reduce oxidative stress and, in particular, MDA levels in order to prevent sustained vascular hyperpermeability in atherosclerosis and diabetes patients.
Highlights
Patients with atherosclerosis and type 2 diabetes often demonstrate elevated endogenous dicarbonyls including malondialdehyde (MDA), glyoxal (GO), and methylglyoxal (MGO) [1]
These substances irreversibly modify proteins in vascular cells leading to micro- and macrovasculopathies that manifest in accelerated atherosclerotic plaque progression, augmented endothelial permeability, and consecutive deterioration of underlying tissues [5]
At concentrations of 150–250 μM, MDA produced a dose-dependent decrease in the total electric impedance of the EA.hy926 cell monolayer measured by the transendothelial electric resistance (TER) assay (Figure 1(a))
Summary
Patients with atherosclerosis and type 2 diabetes often demonstrate elevated endogenous dicarbonyls including malondialdehyde (MDA), glyoxal (GO), and methylglyoxal (MGO) [1]. The major endogenous source of GO and MGO is believed to be high blood glucose and other carbohydrates [4, 5] whereas MDA is produced mainly from polyunsaturated fatty acids (PUFA) during free radical lipoperoxidation This condition accompanies oxidative stress and is typical to both atherosclerosis and diabetes [2, 6]. The aldehyde/carbonyl groups of GO, MGO, and MDA may react with proteins, nucleic acids, and other biopolymers, which critically contributes to the pathological effects of these reactive dicarbonyl species These substances irreversibly modify proteins in vascular cells leading to micro- and macrovasculopathies that manifest in accelerated atherosclerotic plaque progression, augmented endothelial permeability, and consecutive deterioration of underlying tissues [5]. Considering that MDA endogenous levels exceed those of GO or MGO and tend to increase further during lipoperoxidation, it appears important to reduce oxidative stress and, in particular, MDA levels in order to prevent sustained vascular hyperpermeability in atherosclerosis and diabetes patients
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