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From the University of Cincinnati and Cincinnati Veterans Administration
Medical Center, Cincinnati, Ohio.
Correspondence to Gerald W. Dorn II, MD, University of Cincinnati and Cincinnati Veterans Administration Medical Center, 231 Bethesda Ave, ML 0542, Cincinnati, OH 45267-0542. E-mail DornGW{at}ucbeh.san.uc.edu
Background—Receptor-mediated
activation of myocardial Gq signaling is postulated as a biochemical
mechanism transducing pressure-overload hypertrophy. The
specific effects of Gq activation on the functional and morphological
adaptations to pressure overload are not known.
Methods and Results—To determine the effects of intrinsic myocyte
G
Conclusions—Intrinsic cardiac myocyte G
© 1998 American Heart Association, Inc.
Basic Science Reports
Decompensation of Pressure-Overload Hypertrophy in G
q-Overexpressing Mice
q signaling on the left ventricular hypertrophic
response to experimental pressure overload, transgenic mice
overexpressing Gq specifically in the heart (Gq-25) and
nontransgenic siblings underwent microsurgical creation of transverse
aortic coarctation and the morphometric, functional, and molecular
characteristics of these pressure-overloaded hearts were compared at
increasing times after surgery. Before aortic banding, isolated
Gq-25 ventricular myocytes exhibited contractile
depression (depressed +dl/dt and -dl/dt) and Gq-25 hearts showed a
pattern of fetal gene expression similar to the known characteristics
of nontransgenic pressure-overloaded mice. Three weeks after transverse
aortic banding, Gq-25 left ventricles hypertrophied to a similar
extent (
30% increase) as nontransgenic mice. However, whereas
nontransgenic mice exhibited concentric left ventricular
remodeling with maintained ejection performance (compensated
hypertrophy), Gq-25 left ventricles developed eccentric
hypertrophy and ejection performance deteriorated,
ultimately resulting in left heart failure (decompensated
hypertrophy). The signature
hypertrophy-associated progress of fetal cardiac gene
expression observed at baseline in Gq-25 developed after aortic
banding of nontransgenic mice but did not significantly change in
aortic-banded Gq-25 mice. q activation stimulates
fetal gene expression and depresses cardiac myocyte
contractility. Superimposition of the
hemodynamic stress of pressure overload on Gq
overexpression stimulates a maladaptive form of eccentric
hypertrophy that leads to rapid functional decompensation.
Therefore Gq-stimulated cardiac hypertrophy is
functionally deleterious and compromises the ability of the heart to
adapt to increased mechanical load. This finding supports a
reevaluation of accepted concepts regarding the mechanisms for
compensation and decompensation in pressure-overload
hypertrophy.
Key Words: hypertrophy • genetics • morphogenesis • ventricles • pressure
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