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Titolo:
Protein kinase A (PKA)-dependent troponin-I phosphorylation and PKA regulatory subunits are decreased in human dilated cardiomyopathy
Autore:
Zakhary, DR; Moravec, CS; Stewart, RW; Bond, M;
Indirizzi:
Cleveland4195n Fdn, Lerner Res Inst, Dept Mol Cardiol FF10, Cleveland, OH 4 Cleveland Clin Fdn Cleveland OH USA 44195 l Cardiol FF10, Cleveland, OH 4 Case4106tern Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 4 Case Western Reserve Univ Cleveland OH USA 44106 Biophys, Cleveland, OH 4 Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USACleveland Clin Fdn Cleveland OH USA 44195 c Surg, Cleveland, OH 44195 USA Cleveland Clin Fdn, Ctr Anesthesiol Res, Cleveland, OH 44195 USA ClevelandClin Fdn Cleveland OH USA 44195 ol Res, Cleveland, OH 44195 USA
Titolo Testata:
CIRCULATION
fascicolo: 4, volume: 99, anno: 1999,
pagine: 505 - 510
SICI:
0009-7322(19990202)99:4<505:PKA(TP>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
CALCIUM SENSITIVITY; ISOMETRIC TENSION; HEART-FAILURE; CYCLIC-AMP; CATECHOLAMINE; PHOSPHOLAMBAN; DYSFUNCTION; MECHANISM; RECEPTOR;
Keywords:
cardiomyopathy; troponin; enzymes; proteins; receptors, adrenergic, beta;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
23
Recensione:
Indirizzi per estratti:
Indirizzo: Bond, M Cleveland,Clin Fdn, Lerner Res Inst, Dept Mol Cardiol FF10, 9500 Euclid Ave Cleveland Clin Fdn 9500 Euclid Ave Cleveland OH USA 44195 clid Ave
Citazione:
D.R. Zakhary et al., "Protein kinase A (PKA)-dependent troponin-I phosphorylation and PKA regulatory subunits are decreased in human dilated cardiomyopathy", CIRCULATION, 99(4), 1999, pp. 505-510

Abstract

Background-Most studies indicate that failing human hearts have greater baseline myofibrillar Ca2+ sensitivity of tension development than nonfailinghearts. Phosphorylation of cardiac troponin I (TnI) by cAMP-dependent protein kinase (PKA) decreases the affinity of the troponin complex for Ca2+, thus altering the Ca2+ sensitivity of force production. We tested the hypothesis that PKA-dependent TnI phosphorylation is altered in the failing humanheart and investigated changes in PKA regulatory subunits as a potential mechanism. Methods and Results-Using in vitro back-phosphorylation with [gamma-P-32]ATP, we demonstrated a significant (P<0.05) approximate to 25% reduction in baseline PKA-dependent TnI phosphorylation in human hearts with dilated cardiomyopathy (DCM) compared with nonfailing (NF) human hearts. There was no significant difference in cAMP content or maximal PKA activity between DCM and NF hearts, but expression of the regulatory subunits of PKA-I (RI) and PKA-II (RII) was significantly decreased in DCM versus NF hearts (RI by approximate to 40%, P<0.05; RII by approximate to 30%, P<0.01). Conclusions-PKA activity is regulated at the substrate level through interactions of PKA regulatory subunits with A-kinase anchoring proteins. The reduced baseline PKA-dependent phosphorylation of TnI in DCM may be due to decreased expression of RI and RII and consequently reduced anchoring of PKA holoenzyme, These findings provide new evidence of deficiencies in downstream regulation of the beta-adrenergic pathway in the failing human heart andmay account for increased baseline myofibrillar Ca2+ sensitivity.

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Documento generato il 02/04/20 alle ore 18:39:07