© 1997 American Heart Association, Inc.
Articles |
Experimental Diabetes Is Associated With Functional Activation of Protein Kinase C
and Phosphorylation of Troponin I in the Heart, Which Are Prevented by Angiotensin II Receptor Blockade
From the Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY.
Correspondence to Peter M. Buttrick, MD, University of Illinois at Chicago, Section of Cardiology (MC 787), Rm 929, 840 South Wood St, Chicago, IL 60612.
Abstract A cardiomyopathy that is
characterized by an impairment in diastolic relaxation and
a loss of calcium sensitivity of the isolated myofibril has been
described in chronic diabetic animals and humans. To explore a possible
role for protein kinase C (PKC)–mediated
phosphorylation of myofibrillar proteins in this
process, we characterized the subcellular distribution of the major PKC
isoforms seen in the adult heart in cardiocytes isolated from
diabetic rats and determined patterns of
phosphorylation of the major regulatory proteins,
including troponin I (TnI). Rats were made diabetic with a single
injection of streptozotocin, and myocardiocytes were isolated
and studied 3 to 4 weeks later. In nondiabetic animals, 76% of the
PKC isoform was located in the cytosol and 24% was particulate,
whereas in diabetic animals, 55% was cytosolic and 45% was
particulate (P<.05). PKC
, the other major PKC
isoform seen in adult cardiocytes, did not show a change in
subcellular localization. In parallel, TnI
phosphorylation was increased 5-fold in
cardiocytes isolated from the hearts of diabetic animals
relative to control animals (P<.01). The change in
PKC distribution and in TnI phosphorylation in
diabetic animals was completely prevented by rendering the animals
euglycemic with insulin or by concomitant treatment with a
specific angiotensin II type-1 receptor (AT1)
antagonist. Since PKC phosphorylation of
TnI has been associated with a loss of calcium sensitivity of intact
myofibrils, these data suggest that angiotensin II
receptor–mediated activation of PKC may play a role in the contractile
dysfunction seen in chronic diabetes.
Key Words: diabetes mellitus • protein kinase C • angiotensin II type-1 receptor
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