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

Yanggan Wang, Samvit Tandan, Jun Cheng, Chunmei Yang, Lan Nguyen, Jessica Sugianto, Janet L. Johnstone, Yuyang Sun, Joseph A Hill

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Ca2+/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 Ca2+ current (ICa) and slows ICa inactivation. Whether these events are linked mechanistically is unknown. ICa 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 α1c, the channel pore-forming subunit. In failing LV, I Ca density was increased proportionately in both cell types, and the time course of ICa inactivation was slowed. This typical pattern of changes suggested a role of CaMKII. Consistent with this,measurements of CaMKII activity revealed a2-3-fold increase (p < 0.05) in failing LV. To test for a causal link, we measured frequency-dependent ICa 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 ICa. Finally, CaMKII inhibition by internal diffusion of a specific peptide inhibitor reduced ICa 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 ICa remodeling in load-induced heart failure.

Original languageEnglish (US)
Pages (from-to)25524-25532
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number37
DOIs
StatePublished - Sep 12 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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