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Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy

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Abstract

Myocardial hypertrophy is characterized by abnormal intracellular Ca2+ handling and decreased contractile performance. Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates numerous Ca2+ handling proteins and thus can regulate intracellular Ca2+ homeostasis directly. We therefore investigated whether differential expression of CaMKII isoforms occurs with cardiac hypertrophy which might promote an abnormal intracellular Ca2+ homeostasis. We further investigated the potential influence of angiotensin (Ang) II on CaMKII expression levels. Hearts from adult Spontaneously Hypertensive Rats (SHR) and hearts from two transgenic rat models with Ang II-dependent hypertension were studied. The expression of the cardiac CaMKII isoforms δ2, δ3, δ4 and δ9 was determined by RT-PCR and immunoblot methods. Rats transgenic for the mouse Ren-2 gene (mrTGR), SHR and controls were studied at the age of 6 months and rats transgenic for the human renin-angiotensin system (hrTGR) from postnatal day 1 to week 8. SHR and mrTGR had an increased heart/body weight ratio (26 and 25%) compared with controls (p < 0.05). SHR hearts showed significantly increased mRNA levels of δ4 and δ9 (p < 0.05) with no change for δ2 and δ3. mrTGR hearts had a significantly increased δ4 and a significantly decreased δ3 transcript level (p < 0.05) with no change for δ2 and δ9. hrTGR hearts developed severe hypertrophy (42%) after postnatal day 14. The neonatal δ2, δ3 and δ4 isoform expression levels were higher (30–100%) compared with SD controls. The levels decreased with increasing age and equalized to controls at week 8, except for δ4 which started to increase after week 4 (p < 0.05). CaMKIIδ protein levels of all cardiac hypertrophy models were increased in sarcoplasmic reticulum preparations (50–120%) compared with controls (p < 0.05) while the cytosolic levels remained unchanged. Thus, CaMKIIδ isoforms are differentially expressed in cardiac hypertrophy. The fetal δ4 isoform was constantly expressed. CaMKIIδ adopts the fetal phenotype independent of the type of hypertrophic stimulus. The observed alterations of CaMKIIδ isoform patterns may affect intracellular Ca2+ homeostasis and thus contribute to the abnormal contractile phenotype of cardiac hypertrophy.

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Authors and Affiliations

  1. Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straß 10, 13122, Berlin-Buch, Germany

    Dirk Hagemann, Brigitte Hoch, Ernst-Georg Kraus & Peter Karczewski

  2. Franz Volhard Clinic, Lindenberger Weg 80, 13125, Berlin-Buch, Germany

    Jürgen Bohlender

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  1. Dirk Hagemann
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  2. Jürgen Bohlender
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  3. Brigitte Hoch
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  4. Ernst-Georg Kraus
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  5. Peter Karczewski
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Correspondence to Peter Karczewski.

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Hagemann, D., Bohlender, J., Hoch, B. et al. Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy. Mol Cell Biochem 220, 69–76 (2001). https://doi.org/10.1023/A:1010899724222

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