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(Circulation Research. 2005;96:756.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Enhancement of Cardiac Function and Suppression of Heart Failure Progression By Inhibition of Protein Phosphatase 1

Anand Pathak^*, Federica del Monte^*, Wen Zhao, Jo-El Schultz, John N. Lorenz, Ilona Bodi, Doug Weiser, Harvey Hahn, Andrew N. Carr, Faisal Syed, Nirmala Mavila, Leena Jha, Jiang Qian, Yehia Marreez, Guoli Chen, Dennis W. McGraw, E. Kevin Heist, J. Luis Guerrero, Anna A. DePaoli-Roach, Roger J. Hajjar, Evangelia G. Kranias

From the Departments of Pharmacology and Cell Biophysics (A.P., W.Z., J.-E.S., I.B., A.C., J.Q., G.C., E.G.K.), Molecular and Cellular Physiology (J.N.L.), Internal Medicine (H.H., F.S., D.W.M.), and Molecular Genetics and Biochemistry (L.J.), University of Cincinnati, Ohio; Cardiology Division (F.d.M., E.K.H., J.L.G., R.J.H.), Harvard Medical School and Massachusetts General Hospital, Boston, Mass; Department of Pharmacology and Cancer Biology (D.W.), Duke University Medical Center, Durham, NC; Department of Biochemistry and Molecular Biology (N.M., A.A.D.-R.), Indiana University, Indianapolis, Ind.

Correspondence to Evangelia G. Kranias, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, P.O. Box 670575, Cincinnati, OH 45267-0575. E-mail Litsa.Kranias{at}uc.edu

Abnormal calcium cycling, characteristic of experimental and human heart failure, is associated with impaired sarcoplasmic reticulum calcium uptake activity. This reflects decreases in the cAMP-pathway signaling and increases in type 1 phosphatase activity. The increased protein phosphatase 1 activity is partially due to dephosphorylation and inactivation of its inhibitor-1, promoting dephosphorylation of phospholamban and inhibition of the sarcoplasmic reticulum calcium-pump. Indeed, cardiac-specific expression of a constitutively active inhibitor-1 results in selective enhancement of phospholamban phosphorylation and augmented cardiac contractility at the cellular and intact animal levels. Furthermore, the ß-adrenergic response is enhanced in the transgenic hearts compared with wild types. On aortic constriction, the hypercontractile cardiac function is maintained, hypertrophy is attenuated and there is no decompensation in the transgenics compared with wild-type controls. Notably, acute adenoviral gene delivery of the active inhibitor-1, completely restores function and partially reverses remodeling, including normalization of the hyperactivated p38, in the setting of pre-existing heart failure. Thus, the inhibitor 1 of the type 1 phosphatase may represent an attractive new therapeutic target.

Key Words: protein phosphatase 1 • protein phosphatase 1 inhibitor 1 • heart failure • hypertrophy • phospholamban • gene therapy

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