Submitted on May 15, 2008
Revised on August 4, 2008
Accepted on August 4, 2008
Inhibitor-2 prevents phosphatase 1 induced cardiac hypertrophy and mortality
Nicole Brüchert1, Nirmala Mavila, Peter Boknik2, Hideo A Baba, Larissa Fabritz, Ulrich Gergs3, Uwe Kirchhefer4, Paulus Kirchhof5, Marek Matus, Wilhelm Schmitz, Anna A. DePaoli-Roach6*, and Joachim Neumann
1 Westfalische Wilhelms-Universitat
2 University Clinic Muenster
3 Institut fuer Pharmakologie und Toxikologie
4 Pharmacology and Toxicology
5 University Hospital Mnster
6 Indiana University School of Medicine
* To whom correspondence should be addressed. E-mail: adepaoli{at}iupui.edu.
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 the PP1 inhibitor-2 (I-2140). Protein phosphatase activity was increased in PP1 mice but was normalized in double transgenic mice (DT). 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 weight observed in the PP1 mice was normalized in DT. Histological analyses indicated that the PP1 mice had significant cardiac fibrosis, which was absent in DT. Furthermore, PP1 mice exhibited an age-dependent increase in mortality, which was abrogated in DT. 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.
