title: Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.
abstract: 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.
authors.affiliation: 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
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Katrin
authors.initials: K
authors.lastname: Wittköpper
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.forename: Florian
authors.initials: F
authors.lastname: Weinberger
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Ivan
authors.initials: I
authors.lastname: Melnychenko
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.forename: Micha
authors.initials: M
authors.lastname: Peeck
authors.forename: Wolfram H
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Unsöld
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
mesh_terms: 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
chemical_list: 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