ROLE OF CADHERIN INTERNALIZATION IN HYDROGEN PEROXIDE-MEDIATED ENDOTHELIAL PERMEABILITY

Exposure of endothelial monolayers to hydrogen peroxide results in inc reased solute permeability in a time-and dose-dependent fashion. This effect is prevented by either staurosporine, an inhibitor of PKC, or b y Go6976, an inhibitor of ''classical'' PKC isoforms. Immunohistochemi stry of peroxide-treated monolayers illustrates a loss of cadherin sta ining at cell junctions and gap formation predominantly at tri-cellula r junctions. Both staurosporine and Go6976 prevented peroxide-induced gap formation. Peroxide also stimulated internalization of cadherins a s measured by the trypsin protection assay, which was not blocked by s taurosporine or Go6976. These data suggest that peroxide causes: 1) a time-and dose-dependent increase in permeability and dose-dependent in crease in gap formation, both of which are PKC dependent; and 2) promo tes PKC-independent cadherin internalization. These data indicate that cadherin internalization may be part of the mechanism through which o xidants regulate solute permeability. (C) 1998 Elsevier Science Inc.