title: Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current.
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.
authors: Montreal Heart Institute and Department of Medicine, Université de Montéal, Quebec, Canada
authors: Xiao Yan
authors: XY
authors: Qi
authors: Yung-Hsin
authors: YH
authors: Yeh
authors: Ling
authors: L
authors: Xiao
authors: Brett
authors: B
authors: Burstein
authors: Ange
authors: A
authors: Maguy
authors: Denis
authors: D
authors: Chartier
authors: Louis R
authors: LR
authors: Villeneuve
authors: Bianca J J M
authors: BJ
authors: Brundel
authors: Dobromir
authors: D
authors: Dobrev
authors: Stanley
authors: S
authors: Nattel
mesh_terms: D000200:Action Potentials; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004285:Dogs; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013617:Tachycardia, Supraventricular / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D002614:Chelating Agents; C419385:L-type calcium channel alpha(1C); D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D009553:Nimodipine; C017967:W 7; D019703:Calcineurin; D011188:Potassium; D016559:Tacrolimus