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

Myocardial hypertrophy is characterized by abnormal intracellular Ca2+ hand ling and decreased contractile performance. Ca2+/calmodulin-dependent prote in kinase II (CaMKII) phosphorylates numerous Ca2+ handling proteins and th us can regulate intracellular Ca2+ homeostasis directly. We therefore inves tigated whether differential expression of CaMKII isoforms occurs with card iac hypertrophy which might promote an abnormal intracellular Ca2+ homeosta sis. We further investigated the potential influence of angiotensin (Ang) I I 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 d elta (2), delta (3), delta (4) and delta (9) was determined by RT-PCR and i mmunoblot methods. Rats transgenic for the mouse Ren-2 gene (mrTGR), SHR an d 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 wi th controls (p < 0.05). SHR hearts showed significantly increased mRNA leve ls of delta (4) and delta (9) (p < 0.05) with no change for delta (2) and d elta (3). mrTGR hearts had a significantly increased delta (4) and a signif icantly decreased delta (3) transcript level (p < 0.05) with no change for delta (2) and delta (9). hrTGR hearts developed severe hypertrophy (42%) af ter postnatal day 14. The neonatal delta (2), delta (3) and delta (4) isofo rm expression levels were higher (30-100%) compared with SD controls. The l evels decreased with increasing age and equalized to controls at week 8, ex cept for delta (4) which started to increase after week 4 (p < 0.05). CaMKI I delta 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, CaMKII delta isof orms are differentially expressed in cardiac hypertrophy. The fetal delta ( 4) isoform was constantly expressed. CaMKII delta adopts the fetal phenotyp e independent of the type of hypertrophic stimulus. The observed alteration s of CaMKII delta isoform patterns may affect intracellular Ca2+ homeostasi s and thus contribute to the abnormal contractile phenotype of cardiac hype rtrophy.