Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1.

Abstract

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 beta-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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 96 Issue 7 Pg. 756-66 (Apr 15 2005) ISSN: 1524-4571 [Electronic] United States
• PMID: 15746443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium-Binding Proteins
• Enzyme Inhibitors
• Proteins
• phospholamban
• phosphoprotein phosphatase inhibitor 1
• Phosphoprotein Phosphatases
• Protein Phosphatase 1
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium-Transporting ATPases
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium-Binding Proteins (physiology)
• Calcium-Transporting ATPases (physiology)
• Cardiomegaly (etiology, prevention & control)
• Enzyme Inhibitors (therapeutic use)
• Genetic Therapy
• Heart Failure (pathology, physiopathology, prevention & control)
• Mice
• Mice, Transgenic
• Myocardial Contraction
• Phosphoprotein Phosphatases (antagonists & inhibitors, genetics, physiology)
• Phosphorylation
• Protein Phosphatase 1
• Proteins (genetics, physiology)
• Rats
• Sarcoplasmic Reticulum (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Ventricular Remodeling