PMID- 18622016
OWN - NLM
STAT- MEDLINE
DCOM- 20081023
LR  - 20220311
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 37
DP  - 2008 Sep 12
TI  - Ca2+/calmodulin-dependent protein kinase II-dependent remodeling of Ca2+ current 
      in pressure overload heart failure.
PG  - 25524-25532
LID - S0021-9258(20)52594-5 [pii]
LID - 10.1074/jbc.M803043200 [doi]
AB  - 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.
FAU - Wang, Yanggan
AU  - Wang Y
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Tandan, Samvit
AU  - Tandan S
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Cheng, Jun
AU  - Cheng J
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Yang, Chunmei
AU  - Yang C
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Nguyen, Lan
AU  - Nguyen L
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Sugianto, Jessica
AU  - Sugianto J
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Johnstone, Janet L
AU  - Johnstone JL
AD  - Department of Internal Medicine (Cardiology), Dallas, Texas 75390-8573.
FAU - Sun, Yuyang
AU  - Sun Y
AD  - Department of Pediatrics, Emory University, Atlanta, Georgia 30322.
FAU - Hill, Joseph A
AU  - Hill JA
AD  - 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.
LA  - eng
GR  - HL 075173/HL/NHLBI NIH HHS/United States
GR  - HL 080144/HL/NHLBI NIH HHS/United States
GR  - HL 088168/HL/NHLBI NIH HHS/United States
GR  - T35 DK 066141/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080711
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Aorta/metabolism
MH  - Calcium/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
MH  - Heart Failure/*metabolism
MH  - Heart Ventricles/*metabolism
MH  - Male
MH  - Mast Cells/metabolism
MH  - Membrane Potentials
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Biological
MH  - Myocytes, Cardiac/*metabolism
MH  - Patch-Clamp Techniques
MH  - Pressure
PMC - PMC2533065
EDAT- 2008/07/16 09:00
MHDA- 2008/10/24 09:00
PMCR- 2009/09/12
CRDT- 2008/07/16 09:00
PHST- 2008/07/16 09:00 [pubmed]
PHST- 2008/10/24 09:00 [medline]
PHST- 2008/07/16 09:00 [entrez]
PHST- 2009/09/12 00:00 [pmc-release]
AID - S0021-9258(20)52594-5 [pii]
AID - 25524 [pii]
AID - 10.1074/jbc.M803043200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Sep 12;283(37):25524-25532. doi: 10.1074/jbc.M803043200. Epub 
      2008 Jul 11.