Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.
OBJECTIVE
Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response.


RESULTS
We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection.


CONCLUSIONS
Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.
El-Armouche
Ali
A
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. a.el-armouche@uke.uni-hamburg.de
Wittköpper
Katrin
K
Degenhardt
Franziska
F
Weinberger
Florian
F
Didié
Michael
M
Melnychenko
Ivan
I
Grimm
Michael
M
Peeck
Micha
M
Zimmermann
Wolfram H
WH
Unsöld
Bernhard
B
Hasenfuss
Gerd
G
Dobrev
Dobromir
D
Eschenhagen
Thomas
T
D000318:Adrenergic beta-Agonists / Q000009:adverse effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002395:Catecholamines / Q000009:adverse effects*; D004195:Disease Models, Animal; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D007545:Isoproterenol / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002395:Catecholamines; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D019837:Ryanodine Receptor Calcium Release Channel; D000099211:Phospholamban; C021042:protein phosphatase inhibitor-1