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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 3, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn113
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Inhibition of protein phosphatase 1 by inhibitor-2 exacerbates progression of cardiac failure in a model with pressure overload

Stephanie Grote-Wessels1, Hideo A. Baba2, Peter Boknik1, Ali El-Armouche3, Larissa Fabritz4, Hans-Jörg Gillmann5, Dana Kucerova1, Marek Matus1, Frank U. Müller1, Joachim Neumann6, Martina Schmitz5, Frank Stümpel1, Gregor Theilmeier5,7, Jeremias Wohlschlaeger2, Wilhelm Schmitz1 and Uwe Kirchhefer1,*

1 Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Germany
2 Institut für Pathologie und Neuropathologie, Universitätsklinikum Essen, Germany
3 Institut für experimentelle und klinische Pharmakologie, Medical Center Hamburg-Eppendorf, Germany
4 Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, Germany
5 Institut für Anatomie and IZKF, Universitätsklinikum Münster, Germany
6 Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Germany
7 Klinik für Anästhesiologie und Intensivmedizin, Medical University Hannover, Germany

* Correspondence to Uwe Kirchhefer, Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstr. 12, 48149 Münster, Germany Tel.: 0049-251-8355510; Fax: 0049-251-8355501; E-mail: kirchhef{at}uni-muenster.de

Aim: The progression of human heart failure is associated with increased protein phosphatase 1 (PP1) activity, which leads to a higher dephosphorylation of cardiac regulatory proteins such as phospholamban (PLB). In this study, we tested the hypothesis whether the inhibitor-2 (I-2) of PP1 can mediate cardiac protection by inhibition of PP1 activity.

Methods and Results: We induced pressure overload by transverse aortic constriction (TAC) for 28 days in transgenic (TG) mice with heart-directed overexpression of a constitutively active form of I-2 (TGTAC) and wild-type littermates (WTTAC). Both groups were compared to sham-operated mice. TAC treatment resulted in comparable ventricular hypertrophy in both groups. However, TGTAC exhibited a higher atrial mass and an enhanced ventricular mRNA expression of β-myosin heavy chain. The increased afterload was associated with the development of focal fibrosis in TG. Consistent with signs of overt heart failure, fractional shortening and diastolic function were impaired in TGTAC as revealed by Doppler echocardiography. The contractility was reduced in catheterized banded TG mice, which is in line with a depressed shortening of isolated myocytes. This is due to profoundly abnormal cytosolic Ca2+ transients and a reduced stimulation of phosphorylation of phospholamban (PLB)Ser16 after TAC in TG mice. Moreover, administration of isoproterenol was followed by a blunted contractile response in isolated myocytes of TGTAC mice.

Conclusions: These results suggest that cardiac-specific overexpression of a constitutively active form of I-2 is deleterious for cardiac function under conditions of pressure overload. Thus, the long-term inhibition of PP1 by I-2 is not a therapeutic option in the treatment of heart failure.

Time for primary review: 47 days


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