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Cardiovascular Research 2005 68(2):259-267; doi:10.1016/j.cardiores.2005.05.028
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Copyright © 2005, European Society of Cardiology

The cAMP response element binding protein modulates expression of the transient outward current: Implications for cardiac memory

Kornelis W. Patberga,1, Maria N. Obreztchikovaa,1, Sarah F. Giardinab, Aviva J. Symesa, Alexei N. Plotnikova, Jihong Qua, Parag Chandraa, David McKinnone, Shian R. Lioue, Andrew V. Rybina, Iryna Shlapakovaa, Peter Danilo, Jr.a,d, Jay Yangb and Michael R. Rosena,c,d,*

aDepartments of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
bAnesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
cPediatrics, College of Physicians and Surgeons of Columbia University, New York, NY, USA
dCenter for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, PH7West-321, New York, New York 10032, USA
eDepartment of Physiology, State University of Stony Brook, NY, USA

* Corresponding author. Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, PH7West-321, New York, New York 10032, USA. Tel.: +1 212 305 8754; fax: +1 212 305 8351. Email address: mrr1{at}columbia.edu

Objective: Long-term cardiac memory (LTCM), expressed as a specific pattern of T-wave change on ECG, is associated with 1) reduced transient outward potassium current (Ito), 2) reduced mRNA for the pore-forming protein of Ito, Kv4.3, 3) reduced cAMP response element binding protein (CREB), and 4) diminished binding to its docking site on the DNA, the cAMP response element (CRE). We hypothesized a causal link between the decrease of the transcription factor CREB and down-regulation of Ito and one of its channel subunits, KChIP2, in LTCM.

Methods: After three weeks of left ventricular pacing to induce LTCM (8 paced, 7 sham control dogs), epicardial KChIP2 mRNA and protein levels were assessed by real-time PCR and Western blotting. Mimicking the CREB down-regulation in LTCM, CREB was knocked down in situ in other dogs using adenoviral anti-sense. Effects on the action potential notch, reflecting Ito, were investigated in situ using monophasic action potential (MAP) recordings and at the cellular level by the whole-cell patch clamp technique. CREB binding in the KChIP2 promoter region was ascertained by electrophoretic mobility-shift assays.

Results: In LTCM, epicardial KChIP2 mRNA and protein were reduced by 62% and 76%, respectively, compared to shams (p<0.05). CREB binding by the canine KChIP2 promoter region was demonstrated. CREB knockdown led to disappearance of the phase1 notch in MAP and ablation of Ito.

Conclusions: These results strengthen the hypothesis that down-regulation of CREB-mediated transcription underlies the attenuation of epicardial Ito in LTCM. They also emphasize that ventricular pacing exerts effects at a subcellular level contributing to memory and conceivably to other forms of cardiac remodeling.

KEYWORDS CREB; KChIP2; Ventricular pacing; Remodeling; Cardiac memory

1 Contributed equally as first authors.

Time for primary review 25 days


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