Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice.
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.


RESULTS
To determine the effects of intrinsic myocyte G alpha q signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing G alpha q specifically in the heart (G alpha q-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 G alpha q-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and -dl/dt) and G alpha q-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, G alpha q-25 left ventricles hypertrophied to a similar extent (approximately 30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), G alpha q-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 G alpha q-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded G alpha q-25 mice.


CONCLUSIONS
Intrinsic cardiac myocyte G alpha q activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on G alpha q overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore G alpha q-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.
Sakata
Y
Y
University of Cincinnati and Cincinnati Veterans Administration Medical Center, Ohio 45267-0542, USA.
Hoit
B D
BD
Liggett
S B
SB
Walsh
R A
RA
Dorn
G W
GW
D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000503:physiopathology*; D003250:Constriction; D004195:Disease Models, Animal; D004452:Echocardiography; D019204:GTP-Binding Proteins / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000502:physiology; D011312:Pressure; D015398:Signal Transduction / Q000502:physiology; D016276:Ventricular Function
D019204:GTP-Binding Proteins