© 2000 American Heart Association, Inc.
Integrative Physiology |
Transgenic Overexpression of Constitutively Active Protein Kinase C 
Causes Concentric Cardiac Hypertrophy
From the Department of Medicine (Y.T., D.L.K., B.D.H., R.A.W.), Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, and Experimental Research Laboratory, Division of Cardiology (P.P., R.B.), University of Louisville, Louisville, Ky.
Correspondence to Richard A. Walsh, MD, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave, Lakeside Room 3563, Cleveland, OH 44106-5029. E-mail raw19{at}po.cwru.edu
Abstract—To test the hypothesis
that activation of the protein kinase C (PKC) 
isoform leads to
cardiac hypertrophy without failure, we studied transgenic
mice with cardiac-specific overexpression of a constitutively active
mutant of the PKC isoform driven by an 
–myosin heavy chain
promoter. In transgenic mice, the protein level of PKC in heart
tissue was increased 9-fold. There was a 6-fold increase of the
membrane/cytosol ratio, and PKC activity in the membrane fraction was
4.2-fold compared with wild-type mice. The heart weight was increased
by 28%, and upregulation of the mRNA for ß-myosin heavy chain and
-skeletal actin was observed in transgenic mouse hearts.
Echocardiography demonstrated increased anterior
and posterior wall thickness with normal left ventricular
function and dimensions, indicating concentric cardiac
hypertrophy. Isolated cardiomyocyte mechanical
function was slightly decreased, and Ca2+ signals were
markedly depressed in transgenic mice, suggesting that myofilament
sensitivity to Ca2+ was increased. No differences were
observed in either the levels of cardiac Ca2+-handling
proteins or the degree of cardiac regulatory protein
phosphorylation between wild-type and transgenic mice.
Unlike mice with PKCß2 overexpression, transgenic mice
with cardiac-specific overexpression of the active PKC mutant
demonstrated concentric hypertrophy with normal in vivo
cardiac function. Thus, PKC isoforms may play differential functional
roles in cardiac hypertrophy and failure.
Key Words: hypertrophy • signal transduction • transgenic mouse • heart failure • protein kinase C
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