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

J Mol Cell Cardiol. 2013 Jun;59:107-16. doi: 10.1016/j.yjmcc.2013.02.014. Epub 2013 Mar 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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