© 1999 American Heart Association, Inc.
Original Contribution |
Responses of Cardiac Protein Kinase C Isoforms to Distinct Pathological Stimuli Are Differentially Regulated
From the Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Richard A. Walsh, MD, Department of Medicine, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106-5029. E-mail raw19{at}po.cwru.edu
Abstract—Currently at least 11
protein kinase C (PKC) isoforms have been identified and may play
different roles in cell signaling pathways leading to changes in
cardiac contractility, the hypertrophic response, and
tolerance to myocardial ischemia. The purpose of the
present study was to test the hypothesis that responses of
individual PKC isoforms to distinct pathological stimuli were
differentially regulated in the adult guinea pig heart. Isolated hearts
were perfused by the Langendorff method and were exposed to
ischemia, hypoxia, H2O2, or
angiotensin II. Hypoxia and ischemia
induced translocation of PKC isoforms 
, ß2, 
, and
, and H2O2 translocated PKC isoforms ,
ß2, and . Angiotensin II produced
translocation of , ß2, 
, , and isoforms.
Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate
(D609) blocked hypoxia-induced (, ß2, and )
and angiotensin II–induced (, ß2, ,
and ) translocation of PKC isoforms. Inhibition of tyrosine kinase
with genistein blocked translocation of PKC isoforms by hypoxia
(ß2 and ) and by angiotensin II
(ß2). By contrast, neither D609 nor genistein blocked
H2O2-induced translocation of any PKC isoform.
We conclude that hypoxia-induced activation of PKC isoforms is
mediated through pathways involving phospholipase C and tyrosine
kinase, but oxidative stress may activate PKC isoforms
independently of Gq-phospholipase C coupling and tyrosine kinase
signaling. Because oxidative stress may directly activate PKC,
and PKC activation appears to be involved in human heart failure,
selective inhibition of the PKC isoforms may provide a novel
therapeutic strategy for the prevention and treatment of this
pathological process.
Key Words: hypoxia • oxidative stress • ischemia • myocardium • signal transduction
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