Inhibition of protein phosphatase 1 by inhibitor-2 exacerbates progression of cardiac failure in a model with pressure overload.
OBJECTIVE
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. In this study, we tested the hypothesis whether the inhibitor-2 (I-2) of PP1 can mediate cardiac protection by inhibition of PP1 activity.


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 (TG(TAC)) and wild-type littermates (WT(TAC)). Both groups were compared with sham-operated mice. TAC treatment resulted in comparable ventricular hypertrophy in both groups. However, TG(TAC) exhibited a higher atrial mass and an enhanced ventricular mRNA expression of beta-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 TG(TAC) 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 Ca(2+) 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 TG(TAC) 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.
Grote-Wessels
Stephanie
S
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Germany.
Baba
Hideo A
HA
Boknik
Peter
P
El-Armouche
Ali
A
Fabritz
Larissa
L
Gillmann
Hans-Jörg
HJ
Kucerova
Dana
D
Matus
Marek
M
Müller
Frank U
FU
Neumann
Joachim
J
Schmitz
Martina
M
Stümpel
Frank
F
Theilmeier
Gregor
G
Wohlschlaeger
Jeremias
J
Schmitz
Wilhelm
W
Kirchhefer
Uwe
U
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000601:surgery; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006325:Heart Atria / Q000201:enzymology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000201:enzymology; D000099211:Phospholamban; D000097847:Protein Phosphatase Inhibitory Proteins
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D054645:Protein Phosphatase 1; D011506:Proteins; D000099211:Phospholamban; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins