Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.
Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
Wittköpper
Katrin
K
Institute of Experimental and Clinical Pharmacology and Toxicology, Cardiovascular Research Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fabritz
Larissa
L
Neef
Stefan
S
Ort
Katharina R
KR
Grefe
Clemens
C
Unsöld
Bernhard
B
Kirchhof
Paulus
P
Maier
Lars S
LS
Hasenfuss
Gerd
G
Dobrev
Dobromir
D
Eschenhagen
Thomas
T
El-Armouche
Ali
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000502:physiology*; D003433:Crosses, Genetic; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000172:deficiency / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D006339:Heart Rate; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D047908:Intracellular Signaling Peptides and Proteins; C497929:Ppp1r1b protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; C021042:protein phosphatase inhibitor-1; D004318:Doxycycline; D002118:Calcium