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Molecular and Cellular Biology, June 2002, p. 4124-4135, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4124-4135.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Type 1 Phosphatase, a Negative Regulator of Cardiac Function

Andrew N. Carr,1 Albrecht G. Schmidt,1 Yoichi Suzuki,2 Federica del Monte,3 Yoji Sato,1,4 Carita Lanner,2 Kristine Breeden,2 Shao-Ling Jing,5 Patrick B. Allen,6 Paul Greengard,6 Atsuko Yatani,1 Brian D. Hoit,7 Ingrid L. Grupp,1 Roger J. Hajjar,3 Anna A. DePaoli-Roach,2 and Evangelia G. Kranias1*

Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267,1 Department of Biochemistry and Molecular Biology,2 Krannert Institute of Cardiology, Indiana University, Indianapolis, Indiana 46202,5 Cardiology Division, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02129,3 National Institute of Health Sciences, Tokyo 158-8501, Japan,4 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021,6 Division of Cardiology, Case Western Reserve University, Cleveland, Ohio 441067

Received 27 November 2001/ Returned for modification 8 January 2002/ Accepted 13 March 2002

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 ß-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 ß-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.

* Corresponding author. Mailing address: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert B. Sabin Way, P.O. Box 670575, Cincinnati, OH 45267-0575. Phone: (513) 558-2377. Fax: (513) 558-2269. E-mail: Litsa.Kranias{at}uc.edu.

Molecular and Cellular Biology, June 2002, p. 4124-4135, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4124-4135.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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