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Regulation of Thrombin-Induced Lung Endothelial Cell Barrier Disruption by Protein Kinase C Delta.


ABSTRACT: Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKC? isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKC? inhibitory studies (rottlerin), dominant negative PKC? construct and PKC? silencing (siRNA). In addition, we identified PKC? as a signaling mediator upstream of both thrombin-induced MLC phosphorylation and Rho GTPase activation affecting stress fiber formation, cell contraction and loss of EC barrier integrity. Our inhibitor-based studies indicate that thrombin-induced PKC? activation exerts a positive feedback on Rho GTPase activation and contributes to Rac1 GTPase inhibition. Moreover, PKD (or PKC?) and CPI-17, two known PKC? targets, were found to be activated by PKC? in EC and served as modulators of cytoskeleton rearrangement. These studies clarify the role of PKC? in EC cytoskeleton regulation, and highlight PKC? as a therapeutic target in inflammatory lung disorders, characterized by the loss of barrier integrity, such as acute lung injury and sepsis.

SUBMITTER: Xie L 

PROVIDER: S-EPMC4956111 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin), dominant negativ  ...[more]

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