Inhibitor-2 prevents protein phosphatase 1-induced cardiac hypertrophy and mortality.
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-2(140)). 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.
Brüchert
Nicole
N
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany.
Mavila
Nirmala
N
Boknik
Peter
P
Baba
Hideo A
HA
Fabritz
Larissa
L
Gergs
Ulrich
U
Kirchhefer
Uwe
U
Kirchhof
Paulus
P
Matus
Marek
M
Schmitz
Wilhelm
W
DePaoli-Roach
Anna A
AA
Neumann
Joachim
J
D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005355:Fibrosis; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D000097847:Protein Phosphatase Inhibitory Proteins
D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011506:Proteins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins