Deletion of PKCalpha in mice attenuates the thrombin‐induced increase in lung vascular permeability

Abstract

We addressed the role of protein kinase Cα (PKCα) in signaling the increase in lung vascular permeability induced by the mediator thrombin. We used PKCα knockout mice to determine the effect of PKCα deletion on changes in endothelial permeability and adherens junction proteins. We determined microvessel filtration coefficient (Kfc) using the isolated‐perfused mouse lung preparation. Stimulation with PAR‐1 agonist peptide (10 μM) increased Kfc 50% less in the knockout mice than control wild type mice. We quantified vascular endothelial (VE) cadherin levels in mouse lung endothelial cells (MLECs) by Western blot analysis. Thrombin rapidly diminished VE‐cadherin levels in MLECs. PKCα deletion abrogated the VE‐cadherin disruption induced by thrombin. As PKCα activation was known to inhibit Akt, we observed higher Akt activity in PKCα‐deleted MLECs. We also observed that activated PKCζ was markedly increased in PKCα‐deleted MLECs, suggesting compensatory activation of PKCζ. The data demonstrate that PKCα is required to elicit the increase in lung vascular permeability. The mechanism of PKCα‐mediated increase in vascular permeability may involve signaling at the level of VE‐cadherin that promotes the disassembly of adherens junctions.This study is supported by NIH # HL45638