Type 1 phosphatase, a negative regulator of cardiac function

Andrew N. Carr, Albrecht G. Schmidt, Yoichi Suzuki, Federica Del Monte, Yoji Sato, Carita Lanner, Kristine Breeden, Shao Ling Jing, Patrick B. Allen, Paul Greengard, Atsuko Yatani, Brian D. Hoit, Ingrid L. Grupp, Roger J. Hajjar, Anna De Paoli-Roach, Evangelia G. Kranias

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

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 β-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 β-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.

Original languageEnglish (US)
Pages (from-to)4124-4135
Number of pages12
JournalMolecular and Cellular Biology
Volume22
Issue number12
DOIs
StatePublished - 2002
Externally publishedYes

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Phosphoric Monoester Hydrolases
Heart Failure
Adrenergic Agents
Premature Mortality
Dilated Cardiomyopathy
Muscle Cells
Catalytic Domain
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Carr, A. N., Schmidt, A. G., Suzuki, Y., Del Monte, F., Sato, Y., Lanner, C., ... Kranias, E. G. (2002). Type 1 phosphatase, a negative regulator of cardiac function. Molecular and Cellular Biology, 22(12), 4124-4135. https://doi.org/10.1128/MCB.22.12.4124-4135.2002

Type 1 phosphatase, a negative regulator of cardiac function. / Carr, Andrew N.; Schmidt, Albrecht G.; Suzuki, Yoichi; Del Monte, Federica; Sato, Yoji; Lanner, Carita; Breeden, Kristine; Jing, Shao Ling; Allen, Patrick B.; Greengard, Paul; Yatani, Atsuko; Hoit, Brian D.; Grupp, Ingrid L.; Hajjar, Roger J.; De Paoli-Roach, Anna; Kranias, Evangelia G.

In: Molecular and Cellular Biology, Vol. 22, No. 12, 2002, p. 4124-4135.

Research output: Contribution to journalArticle

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, De Paoli-Roach, A & Kranias, EG 2002, 'Type 1 phosphatase, a negative regulator of cardiac function', Molecular and Cellular Biology, vol. 22, no. 12, pp. 4124-4135. https://doi.org/10.1128/MCB.22.12.4124-4135.2002
Carr AN, Schmidt AG, Suzuki Y, Del Monte F, Sato Y, Lanner C et al. Type 1 phosphatase, a negative regulator of cardiac function. Molecular and Cellular Biology. 2002;22(12):4124-4135. https://doi.org/10.1128/MCB.22.12.4124-4135.2002
Carr, Andrew N. ; Schmidt, Albrecht G. ; Suzuki, Yoichi ; Del Monte, Federica ; Sato, Yoji ; Lanner, Carita ; Breeden, Kristine ; Jing, Shao Ling ; Allen, Patrick B. ; Greengard, Paul ; Yatani, Atsuko ; Hoit, Brian D. ; Grupp, Ingrid L. ; Hajjar, Roger J. ; De Paoli-Roach, Anna ; Kranias, Evangelia G. / Type 1 phosphatase, a negative regulator of cardiac function. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 12. pp. 4124-4135.
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