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Type 1 phosphatase, a negative regulator of cardiac function.

Authors: Carr, AN  Schmidt, AG  Suzuki, Y  Del Monte, F  Sato, Y  Lanner, C  Breeden, K  Jing, SL  Allen, PB  Greengard, P  Yatani, A  Hoit, BD  Grupp, IL  Hajjar, RJ  DePaoli-Roach, AA  Kranias, EG 
Citation: Carr AN, etal., Mol Cell Biol 2002 Jun;22(12):4124-35.
Pubmed: (View Article at PubMed) PMID:12024026

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.


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CRRD Object Information
CRRD ID: 737728
Created: 2004-02-26
Species: All species
Last Modified: 2004-02-26
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.