Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure.
Cardiac myosin-binding protein-C (cMyBP-C) is an important regulator of cardiac contractility, and its phosphorylation by PKA is a mechanism that contributes to increased cardiac output in response to beta-adrenergic stimulation. It is presently unknown whether heart failure alters cMyBP-C phosphorylation. The present study determined the level of phosphorylated cMyBP-C in failing human hearts and in a canine model of pacing-induced heart failure. A polyclonal antibody directed against the major phosphorylation site of cMyBP-C (Ser-282) was generated and its specificity was confirmed by PKA phosphorylation with isoprenaline in cardiomyocytes and Langendorff-perfused mouse hearts. Left ventricular myocardial tissue from (i) patients with terminal heart failure (hHF; n=12) and nonfailing donor hearts (hNF; n=6) and (ii) dogs with rapid-pacing-induced end-stage heart failure (dHF; n=10) and sham-operated controls (dNF; n=10) were used for quantification of total cMyBP-C and phospho-cMyBP-C by Western blotting. Total cMyBP-C protein levels were similar in hHF and hNF as well as in dHF and dNF. In contrast, the ratio of phospho-cMyBP-C to total cMyBP-C levels were >50% reduced in hHF and >40% reduced in dHF. In summary, cMyBP-C phosphorylation levels are markedly decreased in human and experimental heart failure. Thus, the compromised contractile function of the failing heart might be in part attributable to reduced cMyBP-C phosphorylation levels.
El-Armouche
Ali
A
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, D-20246, Germany. a.el-armouche@uke.uni-hamburg.de
Pohlmann
Lutz
L
Schlossarek
Saskia
S
Starbatty
Jutta
J
Yeh
Yung-Hsin
YH
Nattel
Stanley
S
Dobrev
Dobromir
D
Eschenhagen
Thomas
T
Carrier
Lucie
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002303:Cardiac Output, Low / Q000139:chemically induced / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003971:Diastole; D004285:Dogs; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D013599:Systole; D020107:Troponin T / Q000378:metabolism; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D020107:Troponin T; D000099211:Phospholamban; D000099163:Myosin Binding Protein C