Determinants of CREB degradation and KChIP2 gene transcription in cardiac memory.
Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to) channel accessory subunit, KChIP2. The KChIP2 decrease is attributed to a decrease in its transcription factor, cyclic adenosine monophosphate response element binding ... protein (CREB).This study sought to determine the mechanisms responsible for the CREB decrease that is initiated by LVP.CM was quantified as T-wave vector displacement in 18 LVP dogs. In 5 dogs, angiotensin II receptor blocker, saralasin, was infused before and during pacing. In 3 dogs, proteasomal inhibitor, lactacystin, was injected into the left anterior descending artery before LVP. Epicardial biopsy samples were taken before and after LVP. Neonatal rat cardiomyocytes (NRCM) were incubated with H(2)O(2) (50 micromol/l) for 1 hour with or without lactacystin.LVP significantly displaced the T-wave vector and was associated with increased lipid peroxidation and increased tissue angiotensin II levels. Saralasin prevented T-vector displacement and lipid peroxidation. CREB was significantly decreased after 2 hours of LVP and was comparably decreased in H(2)O(2)-treated NRCM. Lactacystin inhibited the CREB decrease in LVP dogs and H(2)O(2)-treated NRCM. LVP and H(2)O(2) both induced CREB ubiquitination, and the H(2)O(2)-induced CREB decrease was prevented by knocking down ubiquitin.LVP initiates myocardial angiotensin II production and reactive oxygen species synthesis, leading to CREB ubiquitination and its proteasomal degradation. This sequence of events would explain the pacing-induced reduction in KChIP2, and contribute to altered repolarization and the T-wave changes of cardiac memory.
Mesh Terms:
Action Potentials, Angiotensin II, Animals, Arrhythmias, Cardiac, Blotting, Western, Cardiac Pacing, Artificial, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, Dogs, Heart Conduction System, Ion Channels, Kv Channel-Interacting Proteins, Lipid Peroxidation, Male, Models, Animal, Models, Cardiovascular, Myocardium, Myocytes, Cardiac, Oxidative Stress, Proteasome Endopeptidase Complex, Reactive Oxygen Species, Ubiquitin, Ubiquitination, Ventricular Function, Left, Ventricular Remodeling
Action Potentials, Angiotensin II, Animals, Arrhythmias, Cardiac, Blotting, Western, Cardiac Pacing, Artificial, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, Dogs, Heart Conduction System, Ion Channels, Kv Channel-Interacting Proteins, Lipid Peroxidation, Male, Models, Animal, Models, Cardiovascular, Myocardium, Myocytes, Cardiac, Oxidative Stress, Proteasome Endopeptidase Complex, Reactive Oxygen Species, Ubiquitin, Ubiquitination, Ventricular Function, Left, Ventricular Remodeling
Heart Rhythm
Date: Jul. 01, 2010
PubMed ID: 20346417
View in: Pubmed Google Scholar
Download Curated Data For This Publication
122849
Switch View:
- Interactions 1