Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1.
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.
Pathak
Anand
A
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, USA.
del Monte
Federica
F
Zhao
Wen
W
Schultz
Jo-El
JE
Lorenz
John N
JN
Bodi
Ilona
I
Weiser
Doug
D
Hahn
Harvey
H
Carr
Andrew N
AN
Syed
Faisal
F
Mavila
Nirmala
N
Jha
Leena
L
Qian
Jiang
J
Marreez
Yehia
Y
Chen
Guoli
G
McGraw
Dennis W
DW
Heist
E Kevin
EK
Guerrero
J Luis
JL
DePaoli-Roach
Anna A
AA
Hajjar
Roger J
RJ
Kranias
Evangelia G
EG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015316:Genetic Therapy; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020257:Ventricular Remodeling; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D004791:Enzyme Inhibitors; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D011506:Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C073882:phosphoprotein phosphatase inhibitor 1