Abstract 1367: Altered Transmural Expression Of I Kr In Cardiac Memory Is Regulated By The Transcription Factor, Activator Protein-1

Abstract

Introduction: We previously reported that the transient outward current (I to ) and mRNA and protein levels of its accessory subunit KChIP2 decrease in ventricular pacing-induced cardiac memory (CM). These changes appear dependent on a decrease of the cAMP response element binding protein (CREB). We have also reported that the transmural gradients of the delayed rectifier potassium current component, I kr and the mRNA and protein of its subunit ERG (all showing epicardium (EPI) > endocardium (ENDO)), are diminished in CM. However, there is no CREB binding site in the ERG promoter region to explain the change in ERG. We now tested the hypothesis that 1) the normal transmural gradient of ERG expression in canine left ventricle (LV) is paralleled by a transmural gradient of the Activator protein-1 (AP-1) components c-Jun and c-Fos, and 2) altered transmural expression of c-Jun and c-Fos parallels the altered transmural ERG in CM. Methods: We screened 2000bp upstream from the first exon of ERG for transcription factor binding sites. Then 10 dogs were chronically instrumented with LV posterior wall and LA pacing electrodes. Five underwent 3w AV-sequential pacing (CM), and 5, 3w of atrial pacing (Sham). CM was quantified as change in T wave vector displacement (TVD). At 3w biopsies were taken 1–2 cm from the LV pacing site. Real time PCR was used to determine c-Jun and c-Fos. Results: Screening revealed an AP-1 response element upstream to the ERG promoter region, supporting the hypothesis that c-Jun and c-Fos might be reasonable candidate transcription factors here. TVD increased in CM compared to Sham. As previously, mRNA and protein transmural gradients of ERG decreased in CM. C-jun and c-Fos exhibited transmural gradients, EPI>ENDO, in Sham (Table ). This gradient was lost in CM. Conclusion AP-1 is a transcription factor for ERG and the altered ERG transmural gradient in CM may be regulated by the altered c-Jun and c-Fos gradient. T vector displacement (TVD) and mRNA of c-Jun and c-Fos