ИСТИНА

One of the most important functions of vascular endothelium is the regulation of macromolecule and cell transport from blood stream to the tissues. Disregulation of endothelial barrier function is typical for various inflammatory pathologies. TNF-inducible mechanisms which provide macromolecules transport through endothelium (permeability increase) are bound to destabilization and degradation of protein complexes which compose cell junctions. TNF initiates shedding of VE-cadherin by MMP-9 activation along with β-catenin cleavage. Caspases (particularly caspase-3) are known to take part in β-catenin cleavage but these data are controversial and the confirmation is necessary. We estimated the role of different mechanisms (caspase-dependent β-catenin cleavage and MMP-9-dependent shedding of VE-cadherin) in the increase of endothelial permeability. With the use of mitochondria-targeted antioxidants based on plastoquinone and penetrating cations of SkQ family we studied the role of mitochondrial ROS in the activation of these mechanisms. The shedding of VE-cadherin by MMP-9 did the main contribution in the induction of endothelial permeability. β-catenin cleavage by caspases (including caspase-3) contributes significantly lesser but statistically valid to this process. β-catenin cleavage by caspases but not caspase activation was partially dependent on MMP-9. Mitochondrial ROS participate in the TNF-dependent induction of endothelial permeability. Herewith mitochondrial ROS stimulated both shedding of VE-cadherin by MMP-9 and β-catenin cleavage.