© 1997 American Heart Association, Inc.
Articles |
High Glucose Concentrations Increase Endothelial Cell Permeability via Activation of Protein Kinase C
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin (Germany).
Correspondence to Hermann Haller, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail haller{at}mdc-berlin.de
Abstract Endothelial cell permeability is
impaired in diabetes mellitus and may be increased by high
extracellular glucose concentrations. High glucose activates
protein kinase C (PKC), a family of kinases vital to intracellular
signaling. We tested the hypothesis that high glucose concentration
activates PKC in endothelial cells and leads to
an increase in endothelial cell permeability via
distinct PKC isoforms. Porcine aortic endothelial cells
were used, and the PKC isoforms , 
, 
, 
, and 
were
identified in these cells. Glucose caused a rapid dose-dependent
increase in endothelial cell permeability, with an
EC50 of 17.5 mmol/L. Phorbol 12-myristate
13-acetate (TPA) induced an increase in permeability very similar to
that elicited by glucose. The effect of glucose and TPA was totally
reversed by preincubating the cells with the PKC inhibitors
staurosporine (10-8 mol/L) and Goe
6976 (10-8 mol/L). Downregulation of PKC by
preincubation with TPA for 24 hours also abolished the effect of
glucose and TPA on endothelial cell permeability. High
glucose (20 mmol/L) caused an increase in PKC activity at 2, 10,
and 30 minutes. Cell fractionation and Western blot analysis
showed a glucose-induced translocation of PKC and PKC. Confocal
microscopy confirmed the translocation and showed an association of
PKC and PKC with nuclear structures and the cell membrane.
Specific antisense oligodesoxynucleotides (ODNs) against
PKC reduced the expression of the isoform, abolished the effects of
glucose on endothelial cell permeability completely,
and reduced the TPA effect significantly. In contrast, specific
antisense ODNs against PKC had no effect on glucose-induced
permeability and only a minor effect on the TPA-induced increase in
permeability. We conclude that an increase in extracellular glucose
leads to a rapid dose-dependent increase in endothelial
cell permeability via the activiation of PKC and that this effect is
mediated by the PKC isoform .
Key Words: permeability • glucose • hyperglycemia • protein kinase C • antisense oligodesoxynucleotide
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