Type 1 phosphatase, a negative regulator of cardiac function.
Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired beta-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of beta-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.
Carr
Andrew N
AN
Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Schmidt
Albrecht G
AG
Suzuki
Yoichi
Y
del Monte
Federica
F
Sato
Yoji
Y
Lanner
Carita
C
Breeden
Kristine
K
Jing
Shao-Ling
SL
Allen
Patrick B
PB
Greengard
Paul
P
Yatani
Atsuko
A
Hoit
Brian D
BD
Grupp
Ingrid L
IL
Hajjar
Roger J
RJ
DePaoli-Roach
Anna A
AA
Kranias
Evangelia G
EG
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000503:physiopathology; D002352:Carrier Proteins; D002478:Cells, Cultured; D004722:Endoribonucleases; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016601:RNA-Binding Proteins; C021042:protein phosphatase inhibitor-1; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; C097081:PPP1R8 protein, human; D007545:Isoproterenol