© 2000 American Heart Association, Inc.
Integrative Physiology |
Protein Kinase C Activation Contributes to Microvascular Barrier Dysfunction in the Heart at Early Stages of Diabetes
From the Departments of Surgery and Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, Temple, Tex.
Correspondence to Dr Sarah Yuan, Departments of Surgery and Medical Physiology, Texas A&M University System Health Science Center, 1901 S 1st St, Bldg 4, Temple, TX 76504. E-mail yuan{at}tamu.edu
Abstract—The functional
disturbance of microvasculature is recognized as an initiating
mechanism that underlies the development of various diabetic
complications. Although a causal relationship between microvascular
leakage and tissue damage has been well documented in diabetic kidneys
and eyes, there is a lack of information regarding the barrier function
of coronary exchange vessels in the disease state. The aim of
the present study was to evaluate the permeability property of
coronary microvessels during the early development of
experimental diabetes with a focus on the protein kinase C
(PKC)-dependent signaling mechanism. The apparent permeability
coefficient of albumin (Pa) was measured in isolated and
perfused porcine coronary venules. The administration of high
concentrations of D-glucose induced a dose-dependent
increase in the Pa value, which was prevented by blockage of PKC with
its selective inhibitors bisindolylmaleimide and Goe 6976.
More importantly, an elevated basal permeability to albumin was
observed in coronary venules at the early onset of
streptozotocin-induced diabetes. The hyperpermeability was corrected
with bisindolylmaleimide and the selective PKCß inhibitor
hispidin. Concomitantly, protein kinase assay showed a high PKC
activity in isolated diabetic venules. Immunoblot
analysis of the diabetic heart revealed a significant
subcellular translocation of PKCßII and PKC
from the cytosol to
the membrane, indicating that the specific activity of these isoforms
was preferentially elevated. The results suggest that
endothelial barrier dysfunction attributed to the
activation of PKC occurs at the coronary exchange vessels in
early diabetes.
Key Words: diabetes • microcirculation • permeability • protein kinases
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