Ca2+/calmodulin-dependent protein kinase II-dependent remodeling of Ca2+ current in pressure overload heart failure

J Biol Chem. 2008 Sep 12;283(37):25524-25532. doi: 10.1074/jbc.M803043200. Epub 2008 Jul 11.


Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity is increased in heart failure (HF), a syndrome characterized by markedly increased risk of arrhythmia. Activation of CaMKII increases peak L-type Ca(2+) current (I(Ca)) and slows I(Ca) inactivation. Whether these events are linked mechanistically is unknown. I(Ca) was recorded in acutely dissociated subepicardial and subendocardial murine left ventricular (LV) myocytes using the whole cell patch clamp method. Pressure overload heart failure was induced by surgical constriction of the thoracic aorta. I(Ca) density was significantly larger in subepicardial myocytes than in subendocardial/myocytes. Similar patterns were observed in the cell surface expression of alpha1c, the channel pore-forming subunit. In failing LV, I(Ca) density was increased proportionately in both cell types, and the time course of I(Ca) inactivation was slowed. This typical pattern of changes suggested a role of CaMKII. Consistent with this, measurements of CaMKII activity revealed a 2-3-fold increase (p < 0.05) in failing LV. To test for a causal link, we measured frequency-dependent I(Ca) facilitation. In HF myocytes, this CaMKII-dependent process could not be induced, suggesting already maximal activation. Internal application of active CaMKII in failing myocytes did not elicit changes in I(Ca). Finally, CaMKII inhibition by internal diffusion of a specific peptide inhibitor reduced I(Ca) density and inactivation time course to similar levels in control and HF myocytes. I(Ca) density manifests a significant transmural gradient, and this gradient is preserved in heart failure. Activation of CaMKII, a known pro-arrhythmic molecule, is a major contributor to I(Ca) remodeling in load-induced heart failure.

Publication types

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

MeSH terms

  • Animals
  • Aorta / metabolism
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Heart Failure / metabolism*
  • Heart Ventricles / metabolism*
  • Male
  • Mast Cells / metabolism
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Pressure


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