While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice.

Abstract

OBJECTIVE:

CaMKII contributes to impaired contractility in heart failure by inducing SR Ca(2+)-leak. CaMKII-inhibition in the heart was suggested to be a novel therapeutic principle. Different CaMKII isoforms exist. Specifically targeting CaMKIIδ, the dominant isoform in the heart, could be of therapeutic potential without impairing other CaMKII isoforms.

RATIONALE:

We investigated whether cardiomyocyte function is affected by isoform-specific knockout (KO) of CaMKIIδ under basal conditions and upon stress, i.e. upon ß-adrenergic stimulation and during acidosis.

RESULTS:

Systolic cardiac function was largely preserved in the KO in vivo (echocardiography) corresponding to unchanged Ca(2+)-transient amplitudes and isolated myocyte contractility in vitro. CaMKII activity was dramatically reduced while phosphatase-1 inhibitor-1 was significantly increased. Surprisingly, while diastolic Ca(2+)-elimination was slower in KO most likely due to decreased phospholamban Thr-17 phosphorylation, frequency-dependent acceleration of relaxation was still present. Despite decreased SR Ca(2+)-reuptake at lower frequencies, SR Ca(2+)-content was not diminished, which might be due to reduced diastolic SR Ca(2+)-loss in the KO as a consequence of lower RyR Ser-2815 phosphorylation. Challenging KO myocytes with isoproterenol showed intact inotropic and lusitropic responses. During acidosis, SR Ca(2+)-reuptake and SR Ca(2+)-loading were significantly impaired in KO, resulting in an inability to maintain systolic Ca(2+)-transients during acidosis and impaired recovery.

CONCLUSIONS:

Inhibition of CaMKIIδ appears to be safe under basal physiologic conditions. Specific conditions exist (e.g. during acidosis) under which CaMKII-inhibition might not be helpful or even detrimental. These conditions will have to be more clearly defined before CaMKII inhibition is used therapeutically.

• Authors: Stefan Neef, Can M Sag, Maria Daut, Henrik Bäumer, Clemens Grefe, Ali El-Armouche, Jaime DeSantiago, Laetitia Pereira, Donald M Bers, Johannes Backs, Lars S Maier
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 59 Pg. 107-16 (Jun 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 23473775 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium

Topics

• Acidosis (metabolism)
• Animals
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
• Diastole (genetics, physiology)
• Excitation Contraction Coupling
• Mice
• Mice, Knockout
• Myocytes, Cardiac (cytology, metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Systole (genetics, physiology)