Abstract 422: Ca/calmodulin Kinase II Differentially Modulates Transient Outward Potassium Current in Heart Failure
Ca/Calmodulin kinase II (CaMKII) expression is enhanced in human heart failure (HF). Transgenic mice overexpressing CaMKIIδc (cytosolic isoform, TG) develop HF with increased action potential duration (APD). CaMKII dependent regulation of transient outward potassium current (Ito) may be of relevance. When Ito was measured via patch-clamp in myocytes from TG (4–5 fold overexpression) vs. wild type (WT) littermates, maximal Ito (pA/pF, in I–V curves) was reduced (TG 4.59±0.79, WT 6.69±1.72; N=6 vs. N=6, P<0.05), and was not reversible with acute CaMKII inhibition by 0.1 μmol/l AIP. However, Ito recovery from inactivation was hastened. After 825 ms recovery, the fraction of recovered Ito was 0.91±0.02 for TG vs. 0.85±0.03 for WT (N=7 vs. 8, P<0.05) and AIP slowed this recovery in TG to 0.63±0.12 (N=4, P<0.05). Expression levels of Kv4.2 were significantly reduced, but Kv1.4 expression significantly increased in TG vs. WT in Western blot analysis (N=8 each). APD at 80% repolarization (APD80) was prolonged (TG 23.6±5.9 vs. WT 17.3±2.9 ms, N=7 vs. 7,P<0.05), but not reversible with AIP. To examine CaMKII effects on Ito in a species where Ito is more like human, we analysed Ito in rabbit ventricular myocytes. Acute CaMKIIδc overexpression 4–5 fold via adenovirus-mediated gene transfer (Ad-CaMKII, MOI 100, 24 h, LacZ as control) did not alter Kv4.3 (more abundant than Kv4.2) expression, but significantly increased Kv1.4 expression (N=8 and 12). Maximal Ito (in IV curves) was 1.8±0.36 (Ad-CaMKII) vs. 1.4±0.19 (Ad-LacZ, N=11 each, P=0.08), and not altered by AIP (1.41±0.33). Similar to TG, Ito recovery from inactivation more rapidly in Ad-CaMKII (after 825 ms recovery was 0.72±0.05 vs. 0.62±0.05 in Ad-LacZ, N=13 vs. 11, P<0.05), and reversible with AIP (0.580±.09, N=9, P<0.05). In parallel, APD90 was reduced in Ad-CaMKII vs. LacZ (319±7 vs. 378.±13.2 ms, N=19 vs.16, P<0.05), and reversible with AIP (395.3±6.4 ms,N=11, P<0.05). In conclusion, CaMKIIδc directly increased Kv1.4 expression and function resulting in APD shortening. In TG mice with HF, these effects are counterbalanced by a reduced Kv4.2 expression which prolongs APD. In the face of spatial heterogenic K channel expression these divergent changes may contribute to arrhythmias in HF.