Erschienen in:
01.09.2012 | Original Contribution
Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging
verfasst von:
Stela Florea, Ahmad Anjak, Wen-Feng Cai, Jiang Qian, Elizabeth Vafiadaki, Sarah Figueria, Kobra Haghighi, Jack Rubinstein, John Lorenz, Evangelia G. Kranias
Erschienen in:
Basic Research in Cardiology
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Ausgabe 5/2012
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Abstract
The activity of protein phosphatase-1 (PP1) inhibitor-1 (I-1) is antithetically modulated by the cAMP-protein kinase A (PKA) and Ca2+-protein kinase C (PKC) signaling axes. β-adrenergic (β-AR) stimulation results in PKA-phosphorylation of I-1 at threonine 35 (Thr35) and depressed PP1 activity, while PKC phosphorylation at serine 67 (Ser67) and/or Thr75 increases PP1 activity. In heart failure, pThr35 is decreased while pSer67 and pThr75 are elevated. However, the role of Ser67/Thr75 phosphorylation in vivo and its effects on Ca2+-cycling are not known. Thus, our aim was to investigate the functional significance of Ser67 and Thr75 phosphorylation in intact hearts. We generated transgenic mice (TG) with cardiac-specific overexpression of constitutively phosphorylated I-1 at Ser67 and Thr75 (S67D/T75D) and evaluated cardiac function. The S67D/T75D cardiomyocytes exhibited significantly depressed Ca2+-kinetics and contractile parameters, compared with wild-type (WT) cells. The decreased Ca2+-cycling was associated with a 27 % increase in PP1 activity, no alterations in PP2 activity and impaired phosphorylation of myosin-binding protein-C (MyBPC). Upon aging, there was cardiac remodeling associated with increases in systolic and diastolic left ventricular internal diameter dimensions (at 16 months), compared with WTs. The results indicate that phosphorylation of I-1 at Ser67 and Thr75 is associated with increased PP1 activity and depressed cardiomyocyte Ca2+-cycling, which manifests in geometrical alterations over the long term. Thus, hyperphosphorylation of these sites in failing hearts may contribute to deteriorative remodeling.