Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure.
Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.
Rothermel
Beverly A
BA
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573, USA.
Berenji
Kambeez
K
Tannous
Paul
P
Kutschke
William
W
Dey
Asim
A
Nolan
Bridgid
B
Yoo
Ki-Dong
KD
Demetroulis
Elaine
E
Gimbel
Michael
M
Cabuay
Barry
B
Karimi
Mohsen
M
Hill
Joseph A
JA
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology*; D002312:Cardiomyopathy, Hypertrophic / Q000473:pathology; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology; D006331:Heart Diseases / Q000473:pathology; D006333:Heart Failure / Q000473:pathology; D006439:Hemodynamics; D006984:Hypertrophy; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011312:Pressure; D012313:RNA / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D019703:Calcineurin; D002118:Calcium