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European Journal of Heart Failure 2007 9(11):1077-1080; doi:10.1016/j.ejheart.2007.09.006
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© 2007 European Society of Cardiology

Long-term β-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart

Ali El-Armouchea,*,1, Fabian Gochta,1, Elmar Jaeckelb, Katrin Wittköppera, Micha Peecka and Thomas Eschenhagena,*

a Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany
b Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover Germany

* Corresponding authors. E-mail address: a.el-armouche{at}uke.uni-hamburg.de t.eschenhagen{at}uke.uni-hamburg.de


  Abstract

Desensitization of the β-adrenoceptor/cAMP/PKA pathway is a hallmark of heart failure. Inhibitor-1 (I-1) acts as a conditional amplifier of β-adrenergic signalling downstream of PKA by inhibiting type-1 phosphatases in the PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus presumably contributes to β-adrenergic desensitization. To test whether I-1 downregulation is a consequence of excessive adrenergic drive in heart failure, rats were treated via minipumps with isoprenaline 2.4mg/kg/day (ISO) or 0.9% NaCl for 4days. As expected, chronic ISO increased heart-to-body weight ratio by ~40% and abolished the inotropic response to acute ISO in papillary muscles by ~50%. In the ISO-treated hearts I-1 mRNA and protein levels were decreased by 30% and 54%, respectively. This was accompanied by decreased phospholamban phosphorylation (–40%), a downstream target of I-1, and a reduction in 45Ca2+ uptake (–54%) in membrane vesicles. Notably, phospholamban phosphorylation correlated significantly with I-1 protein levels indicating a causal relationship. We conclude that I-1 downregulation in heart failure is likely a consequence of the increased sympathetic adrenergic drive and participates in desensitization of the β-adrenergic signalling cascade.

Key Words: Phosphatase inhibitor-1 • Phospholamban • Beta-adrenergic signalling

Received June 14, 2007; Revised August 22, 2007; Accepted September 13, 2007

1 These authors contributed equally to this work.


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