Published online before print July 31, 2003, doi: 10.1161/01.RES.0000088785.24381.2F
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Submitted on March 26, 2003
Revised on July 1, 2003
Accepted on July 17, 2003
Cardiac Memory Is Associated With Decreased Levels of the Transcriptional Factor CREB Modulated by Angiotensin II and Calcium
Kornelis W. Patberg ;
From the Departments of Pharmacology, Pediatrics and Anesthesiology, Center for Molecular Therapeutics; College of Physicians and Surgeons of Columbia University, New York, NY.
* To whom correspondence should be addressed. E-mail: mrr1{at}columbia.edu.
Cardiac memory (CM) has short- (STCM) and long-term (LTCM) components modulated by calcium and angiotensin II. LTCM is associated with reduced Ito and Kv4.3 mRNA levels. Because the cAMP response element binding protein, CREB, contributes to CNS memory transcription, we hypothesized that it might be a transcriptional factor in CM, influenced by calcium and angiotensin II. We studied STCM in dogs that were AV sequentially paced (AVP) for 2 hours or sham-operated. STCM was evaluated with ECG and vectorcardiogram (VCG), and subepicardial biopsies were taken at 5 to 120 minutes and investigated for CREB. LTCM was studied in dogs paced for 3 weeks and in sham controls. At 3 weeks the heart was excised, biopsies obtained, and CRE binding tested. STCM induction occurred in AVP dogs but not in sham or AVP dogs treated with saralasin or nifedipine. Nuclear CREB was significantly decreased at 2 hours in the AVP no-drug group only. LTCM dogs manifested reduced binding of nuclear proteins to CRE, and CRE binding activity in the promoter region of Kv4.3. In conclusion, there is an association between STCM induction and decreased nuclear CREB that is angiotensin-modulated and calcium-dependent. Moreover, the decreased CRE binding after 3 weeks of AVP combined with CRE binding activity in the Kv4.3 promoter can explain the Kv4.3 mRNA and Ito downregulation that characterize LTCM.
Key words: ventricular pacing • CREB • transcription factors • cardiac memory • remodeling
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