Abstract 18209: The Effect of CaMKIIdelta Knockout on Cardiac E-C Coupling in Heart Failure
Background: CaMKII plays an important role in regulating cardiac excitation-contraction (E-C) coupling. Excessive CaMKII activation is linked to the development of cardiomyopathy and dysfunction of E-C coupling. Thus, CaMKII has been proposed to be a therapeutic target.
Objective: we studied the effects of chronic CaMKII inhibition on cardiac Ca2+ handling and cell twitch in heart failure (HF) ventricular myocytes.
Method and Results: Pressure-overload HF was produced in the wild type (WT) and CaMKIIdelta knockout (KO) mice by severe thoracic aortic banding (sTAB). HF mice were selected by the criteria of left ventricular (LV) ejection fraction (EF) <40%. Owing to the knockout of the predominant CaMKIIdelta, the total CaMKII activity was significantly reduced in KO HF LV with the total CaMKII activity of 1.32 ± 0.21 pmol/min/μg for KO HF LV vs. 6.33 ± 1.10 pmol/min/μg for WT HF LV. The total CaMKII activity in KO HF LV was even 40% lower than the CaMKII activity in normal WT LV (2.18 ± 0.62 pmol/min/μg). In myocytes isolated from KO HF LV, SR Ca2+ leak was significantly reduced and the SR Ca2+ contents were increased compared to WT HF myocytes, especially at higher pacing rate. The magnitude of Ca2+ transient was increased whereas a significantly slowed Ca2+ transient decay phase was observed in KO HF LV myocytes. The time to 50% decay was 71 ± 6.0 ms in KO HF myocytes compared to 41 ± 2.0 ms in WT HF myocytes (p < 0.05). Consistent with these changes, the magnitude of sarcomere shortening was increased but the time course of sarcomere relaxation was slowed in KO HF myocytes. The slowing of relaxation was more prominent at higher pacing rate.
Conclusions: This is the first model of HF with genetic CaMKII inhibition. Chronic inhibition of CaMKII reduces SR Ca2+ leak and increases SR Ca2+ contents and contractility in HF LV but aggravates cellular relaxation, especially at fast pacing rate. These results support the strategy of CaMKII inhibition in HF but also implicate physiologic level of CaMKII activity in maintaining normal ventricular relaxation.
- © 2010 by American Heart Association, Inc.