Cardiovascular Research Advance Access first published online on August 8, 2008
This version [Corrected Proof] published online on August 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn208
Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy
1 Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
2 Department of Cardiology and Pneumology, Georg-August-University of Göttingen, Göttingen, Germany
3 Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany
* Corresponding authors. Tel: +49 40 42803 2180; fax: +49 40 42803 4876. E-mail address: a.el-armouche{at}uke.uni-hamburg.de (A.El-A.) or t.eschenhagen{at}uke.uni-hamburg.de (T.E.)
Aims: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of β-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 β-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response.
Methods and 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 β-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 β-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute β-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/Ca2+ release channel and the sarcoplasmic reticulum (SR) Ca2+-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca2+ release and Ca2+ uptake and thus stabilize the SR and account for the protection.
Conclusion: 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.
KEYWORDS Inhibitor-1; Catecholamines; Arrhythmias; Cardiac hypertrophy
Time for primary review: 19 days