TY - JOUR
T1 - Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase
AU - Pathak, Anand
AU - Del Monte, Federica
AU - Zhao, Wen
AU - Schultz, Jo El
AU - Lorenz, John N.
AU - Bodi, Ilona
AU - Weiser, Doug
AU - Hahn, Harvey
AU - Carr, Andrew N.
AU - Syed, Faisal
AU - Mavila, Nirmala
AU - Jha, Leena
AU - Qian, Jiang
AU - Marreez, Yehia
AU - Chen, Guoli
AU - McGraw, Dennis W.
AU - Heist, E. Kevin
AU - Guerrero, J. Luis
AU - DePaoli-Roach, Anna A.
AU - Hajjar, Roger J.
AU - Kranias, Evangelia G.
PY - 2005/4/15
Y1 - 2005/4/15
N2 - 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 β-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.
AB - 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 β-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.
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U2 - 10.1161/01.RES.0000161256.85833.fa
DO - 10.1161/01.RES.0000161256.85833.fa
M3 - Article
C2 - 15746443
AN - SCOPUS:20244377242
SN - 0009-7330
VL - 96
SP - 756
EP - 766
JO - Circulation research
JF - Circulation research
IS - 7
ER -