Enhanced protein phosphorylation in hypertensive hypertrophy

Objective: Chronic pressure overload in spontaneously hypertensive rats (SHR) is accompanied by heart hypertrophy and signs of heart failure. Since there is growing evidence for a possible pathophysiological role of altered protein phosphorylation in heart hypertrophy and failure, we studied here cardiac regulatory phosphoproteins and the kinases and phosphatases which regulate their phosphorylation state. Methods: The experiments were performed in ventricles of SHR (12–13 weeks old) and age-matched normotensive Wistar–Kyoto rats (WKY). Results: Basal as well as isoproterenol (Iso)-stimulated force of contraction (FOC) was markedly decreased in isolated electrically driven papillary muscles of SHR. Iso (3 μmol/l, 10 min) increased FOC by 0.91±0.20 mN in SHR and by 3.88±0.52 mN in WKY, respectively. Ca2+-uptake by sarcoplasmic reticulum (SR) at low ionized Ca2+-concentration was increased in homogenates from SHR. This was not due to altered expression of phospholamban (PLB), SR-Ca2+-ATPase and calsequestrin. However, PLB-phosphorylation at threonine-17 (PLB-PT-17) and the activity of Ca2+/calmodulin dependent protein kinase (Ca2+/Cam-PK) was increased in SHR. In addition, we found an enhanced protein kinase A (PKA)-dependent phosphorylation 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 or type 2A between SHR and WKY. Conclusions: It is suggested that increased Ca2+/Cam-PK-activity with resulting increase of PLB-PT-17 enhanced SR-Ca2+-uptake in SHR and might contribute to the pathophysiological changes in cardiac hypertrophy of SHR.