title: Ca2+/calmodulin-dependent protein kinase II-dependent remodeling of Ca2+ current in pressure overload heart failure.
abstract: 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.
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Yanggan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Samvit
authors.initials: S
authors.lastname: Tandan
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Lan
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sugianto
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Johnstone
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia 30322.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8573 and the. Electronic address: joseph.hill@utsouthwestern.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011312:Pressure
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium