Abstract
Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
Highlights
Heart failure is among the most frequent causes of morbidity and mortality worldwide and is, despite improved treatment options, associated with poor prognosis
We found that expression of both variants improved cardiac contractility in young mice at rest but was deleterious and arrhythmogenic under catecholaminergic stress
All mice were backcrossed to C57BL/6J (5–6 generations) and crossed with Ppp1r1a KO mice until they were on a complete homozygote Ppp1r1a-null background
Summary
Heart failure is among the most frequent causes of morbidity and mortality worldwide and is, despite improved treatment options, associated with poor prognosis. New drug principles targeting neurohumoral activation mechanisms, such as antagonists of endothelin receptors, TNF-α or IL-6, and statins, failed to improve survival in clinical studies. Two of the best studied alterations of failing myocyte function are (a) desensitization of the β-adrenergic signaling system [1, 2] and (b) alterations of intracellular Ca2+ handling [3, 4]. The latter include decreased diastolic sarcoplasmic reticulum (SR) Ca2+ uptake via the SR Ca2+ ATPase (SERCA2a) and relatively increased
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