Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts.
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 beta-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.


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.
El-Armouche
Ali
A
Institute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Pamminger
Torsten
T
Ditz
Diana
D
Zolk
Oliver
O
Eschenhagen
Thomas
T
D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D016022:Case-Control Studies; D004722:Endoribonucleases; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D011817:Rabbits; D051381:Rats; D019210:Troponin I / Q000032:analysis / Q000378:metabolism; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004722:Endoribonucleases; D047908:Intracellular Signaling Peptides and Proteins; D010749:Phosphoprotein Phosphatases; D016601:RNA-Binding Proteins; D019210:Troponin I; D000099211:Phospholamban; C021042:protein phosphatase inhibitor-1; C097081:PPP1R8 protein, human