Mitochondria-Targeted Antioxidant SkQR1 Reduces TNF-Induced Endothelial Permeability in vitro
Prolonged or excessive increase in the circulatory level of proinflammatory tumor necrosis factor (TNF) leads to endothelial abnormal activation and subsequent damage. TNF at high concentrations causes apoptosis of endothelial cells. Previously, using the mitochondria-targeted antioxidants of the SkQ family, we showed that apoptosis of endothelial cells is dependent on the production of reactive oxygen species (ROS) in mitochondria (mito-ROS). Now we have found that TNF at low concentrations does not cause cell death but activates caspase-3 and caspase-depen- dent increase in endothelial permeability in vitro. This effect is probably due to the cleavage of P-catenin - an adherent junction protein localized in the cytoplasm. We have also shown that the main contribution to the TNF-induced increase in endothelial permeability is due to the VE-cadherin shedding by the extracellular matrix metalloprotease 9 (MMP9). The mechanisms of caspase-3 and MMP9 activation are probably not related to each other since caspase inhibition did not affect VE-cadherin cleavage and MMP9 inhibition had no effect on the caspase-3 activation. Mitochondria-targeted antioxidant SkQRl inhibited TNF-induced increase in endothelial permeability. SkQRl inhibited caspase-3 activation, P-catenin cleavage, and MMP9-dependent VE-cadherin shedding. The data suggest that mito-ROS are involved in the increase of endothelial permeability due to the activation of both caspase-depen- dent cleavage of intracellular proteins and of MMP9-dependent cleavage of the transmembrane cell-to-cell contact proteins.