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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1527.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Counter Regulatory Effects of PKC_βII and PKC on Coronary Endothelial Permeability

Nathalie Gaudreault; Rachel M. Perrin; Mingzang Guo; Chase P. Clanton; Mack H. Wu; Sarah Y. Yuan

From the Division of Research, Department of Surgery, University of California Davis School of Medicine, Sacramento.

Correspondence to Sarah Yuan, MD, PhD, Professor and Director of Research, Department of Surgery, University of California Davis School of Medicine, 4625 2nd Avenue, Room 3006, Sacramento, CA 95817. E-mail sarhayuan{at}ucdavis.edu

Objective— The aim of this study was to examine the endothelial distribution and activity of selected PKC isoforms in coronary vessels with respect to their functional impact on endothelial permeability under the experimental conditions relevant to diabetes.

Methods and Results— En face immunohistochemistry demonstrated a significant increase of PKC_βII and decrease of PKC expression in coronary arterial endothelium of Zucker diabetic rats. To test whether changes in PKC expression alter endothelial barrier properties, we measured the transcellular electric resistance in human coronary microvascular endothelial monolayers and found that either PKC_βII overexpression or PKC inhibition disrupted the cell–cell adhesive barrier. Three-dimensional fluorescence microscopy revealed that hyperpermeability was caused by altered PKC activity in association with distinct translocation of PKC_βII to the cell–cell junction and PKC localization to the cytosol. Further analyses in fractionated endothelial lysates confirmed the differential redistribution of these isozymes. Additionally, FRET analysis of PKC subcellular dynamics demonstrated a high PKC_βII activity at the cell surface and junction, whereas PKC activity is concentrated in intracellular membrane organelles.

Conclusion— Taken together, these data suggest that PKC_βII and PKC counter-regulate coronary endothelial barrier properties by targeting distinctive subcellular sites. Imbalanced PKC_βII/PKC expression and activity may contribute to endothelial hyperpermeability and coronary dysfunction in diabetes.

Key Words: diabetes • inflammation • permeability • protein kinase • FRET

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