Enhanced protein phosphorylation in hypertensive hypertrophy

doi:10.1016/S0008-6363(01)00346-7

Cardiovascular Research 2001 51(4):717-728; doi:10.1016/S0008-6363(01)00346-7
© 2001 by European Society of Cardiology

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Enhanced protein phosphorylation in hypertensive hypertrophy

Peter Bokník^a^,*, Ingrid Heinroth-Hoffmann^b, Uwe Kirchhefer^a, Jörg Knapp^a, Bettina Linck^a, Hartmut Lüss^a, Thorsten Müller^a, Wilhelm Schmitz^a, Otto-Erich Brodde^b and Joachim Neumann^a

^aInstitut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Domagkstraße 12, D-48129 Münster, Germany
^bInstitut für Pharmakologie und Toxikologie, Martin-Luther-Universität, Magdeburger Straße 4, D-06097 Halle, Germany

^* Corresponding author. Tel.: +49-251-835-5517; fax: +49-251-835-5501 boknik{at}uni-muenster.de

Objective: Chronic pressure overload in spontaneously hypertensiverats (SHR) is accompanied by heart hypertrophy and signs ofheart failure. Since there is growing evidence for a possiblepathophysiological role of altered protein phosphorylation inheart hypertrophy and failure, we studied here cardiac regulatoryphosphoproteins and the kinases and phosphatases which regulatetheir phosphorylation state. Methods: The experiments were performedin ventricles of SHR (12–13 weeks old) and age-matchednormotensive Wistar–Kyoto rats (WKY). Results: Basal aswell as isoproterenol (Iso)-stimulated force of contraction(FOC) was markedly decreased in isolated electrically drivenpapillary muscles of SHR. Iso (3 µmol/l, 10 min) increasedFOC by 0.91±0.20 mN in SHR and by 3.88±0.52 mNin WKY, respectively. Ca²⁺-uptake by sarcoplasmic reticulum(SR) at low ionized Ca²⁺-concentration was increased in homogenatesfrom SHR. This was not due to altered expression of phospholamban(PLB), SR-Ca²⁺-ATPase and calsequestrin. However, PLB-phosphorylationat threonine-17 (PLB-PT-17) and the activity of Ca²⁺/calmodulindependent protein kinase (Ca²⁺/Cam-PK) was increased in SHR.In addition, we found an enhanced protein kinase A (PKA)-dependentphosphorylation of the inhibitory subunit of troponin (TnI).In contrast, there was no difference in the activity or expression(protein- and mRNA-level) of protein phosphatases type 1 ortype 2A between SHR and WKY. Conclusions: It is suggested thatincreased Ca²⁺/Cam-PK-activity with resulting increase of PLB-PT-17enhanced SR-Ca²⁺-uptake in SHR and might contribute to the pathophysiologicalchanges in cardiac hypertrophy of SHR.

KEYWORDS Contractile function; Gene expression; Hypertrophy; Protein kinases; Protein phosphorylation; SR (function)

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