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Physiol. Genomics 23: 18-27, 2005. First published July 20, 2005; doi:10.1152/physiolgenomics.00061.2005
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Translational Physiology

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure

¹ Donald W. Reynolds Cardiovascular Clinical Research Center and ² Division of Cardiology, Department of Internal Medicine, and ³ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas; and Departments of ⁴ Internal Medicine and ⁵ Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa

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.

signal transduction; myocardium

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