Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation.
The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.
['Makarenko|Vladislav V|VV|', 'Usatyuk|Peter V|PV|', 'Yuan|Guoxiang|G|', 'Lee|May M|MM|', 'Nanduri|Jayasri|J|', 'Natarajan|Viswanathan|V|', 'Kumar|Ganesh K|GK|', 'Prabhakar|Nanduri R|NR|']
D002478:Cells, Cultured D003599:Cytoskeleton D017097:Electric Impedance D042783:Endothelial Cells D004789:Enzyme Activation D015971:Gene Expression Regulation, Enzymologic D006801:Humans D000860:Hypoxia D007365:Intercellular Junctions D008168:Lung D020929:Mitogen-Activated Protein Kinase Kinases D018384:Oxidative Stress D010100:Oxygen D010766:Phosphorylation D017382:Reactive Oxygen Species D013997:Time Factors
microvascular endothelial cells junction proteins cytoskeleton proteins oxidative stress