© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts
aInstitute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
bFriedrich-Alexander-University, Erlangen-Nuremberg, Germany
* Corresponding author. Tel.: +49-40-42803-2180; fax: +49-40-42803-4876. t.eschenhagen{at}uke.uni-hamburg.de
Objective: The protein phosphatase inhibitor-1 (I-1) is a highly specific and potent inhibitor of type 1 phosphatases (PP1) that is active only in its protein kinase A (PKA)-phosphorylated form. I-1 ablation decreases, I-1 overexpression sensitizes β-adrenergic signaling in the heart. It is controversial whether I-1 expression is altered in human heart failure (HF), likely because its detection in heart is difficult due to its low abundance. Methods and results: I-1 was >500-fold enriched from left ventricular myocardium (LVM) from patients with terminal HF (n = 16) and non-failing controls (NF, n = 5) and quantified with an affinity-purified I-1 and a I-1 phosphospecific antiserum. In non-failing I-1 protein levels amounted to 126 fmol/mg protein. In failing hearts, I-1 protein levels were reduced by 58% and I-1 phosphorylation by 77% (P<0.001 vs. NF). I-1 phosphorylation correlated well with serine-16 phosphorylation of phospholamban (PLB) in the same hearts (P<0.001). In contrast, PLB, troponin I (TnI) and PP1 protein and TnI phosphorylation levels did not differ between HF and NF. Conclusions: The results suggest that the reduction in I-1 protein and phosphorylation in failing human hearts leads to increased phosphatase activity which in turn may result in reduced phosphorylation of cardiac proteins such as PLB.
KEYWORDS Heart failure; Protein phosphatases; Phospholamban; Troponin I; Adrenergic signal transduction
1 Both authors contributed equally to this work.
Time for primary review 26 days
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