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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1539    most recent 00515.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Brüchert, N. Articles by Neumann, J. PubMed PubMed Citation Articles by Brüchert, N. Articles by Neumann, J.

Inhibitor-2 prevents protein phosphatase 1-induced cardiac hypertrophy and mortality

¹Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany; ²Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and ³Institut für Pathologie, Universität Essen-Duisburg, Essen, ⁴Medizinische Klinik und Poliklinik C, Westfälische Wilhelms-Universität, Münster, and ⁵Institut für Pharmakologie und Toxikologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany

Submitted 15 May 2008 ; accepted in final form 4 August 2008

Cardiac-specific overexpression of the catalytic subunit of protein phosphatase type 1 (PP1) in mice results in hypertrophy, depressed contractility, propensity to heart failure, and premature death. To further address the role of PP1 in heart function, PP1 mice were crossed with mice that overexpress a functional COOH-terminally truncated form of PP1 inhibitor-2 (I-2¹⁴⁰). Protein phosphatase activity was increased in PP1 mice but was normalized in double transgenic (DT) mice. The maximal rates of contraction (+dP/dt) and of relaxation (–dP/dt) were reduced in catheterized PP1 mice but normalized in DT mice. Similar contractile abnormalities were observed in isolated, perfused work-performing hearts and in whole animals by means of echocardiography. The increased absolute and relative heart weights observed in PP1 mice were normalized in DT mice. Histological analyses indicated that PP1 mice had significant cardiac fibrosis, which was absent in DT mice. Furthermore, PP1 mice exhibited an age-dependent increase in mortality, which was abrogated in DT mice. These results indicate that I-2 overexpression prevents the detrimental effects of PP1 overexpression in the heart and further underscore the fundamental role of PP1 in cardiac function. Therefore, PP1 inhibitors such as I-2 could offer new therapeutic options to ameliorate the deleterious effects of heart failure.

transgenic mice; contractility; heart failure; drug target