Abstract
Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.
Original language | English |
---|---|
Pages (from-to) | 845-54 |
Number of pages | 10 |
Journal | Circulation Research |
Volume | 103 |
Issue number | 8 |
DOIs | |
Publication status | Published - 10 Oct 2008 |
Keywords
- Action Potentials
- Animals
- Calcineurin/metabolism
- Calcium Channel Blockers/pharmacology
- Calcium Channels, L-Type/drug effects
- Calcium Signaling/drug effects
- Calmodulin/antagonists & inhibitors
- Cardiac Pacing, Artificial
- Cells, Cultured
- Chelating Agents/pharmacology
- Dogs
- Egtazic Acid/analogs & derivatives
- Heart Atria/metabolism
- Myocytes, Cardiac/drug effects
- NFATC Transcription Factors/metabolism
- Nimodipine/pharmacology
- Potassium/metabolism
- RNA, Messenger/metabolism
- Sulfonamides/pharmacology
- Tachycardia, Supraventricular/metabolism
- Tacrolimus/pharmacology
- Time Factors
- Transcription, Genetic