Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current.
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.
Qi
Xiao Yan
XY
Montreal Heart Institute and Department of Medicine, Université de Montéal, Quebec, Canada
Yeh
Yung-Hsin
YH
Xiao
Ling
L
Burstein
Brett
B
Maguy
Ange
A
Chartier
Denis
D
Villeneuve
Louis R
LR
Brundel
Bianca J J M
BJ
Dobrev
Dobromir
D
Nattel
Stanley
S
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
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