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

Nicole Brüchert, Nirmala Mavila, Peter Boknik, Hideo A. Baba, Larissa Fabritz, Ulrich Gergs, Uwe Kirchhefer, Paulus Kirchhof, Marek Matus, Wilhelm Schmitz, Anna A. DePaoli-Roach, Joachim Neumann

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H1539-H1546
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 1 2008

Keywords

  • Contractility
  • Drug target
  • Heart failure
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Brüchert, N., Mavila, N., Boknik, P., Baba, H. A., Fabritz, L., Gergs, U., Kirchhefer, U., Kirchhof, P., Matus, M., Schmitz, W., DePaoli-Roach, A. A., & Neumann, J. (2008). Inhibitor-2 prevents protein phosphatase 1-induced cardiac hypertrophy and mortality. American Journal of Physiology - Heart and Circulatory Physiology, 295(4), H1539-H1546. https://doi.org/10.1152/ajpheart.00515.2008