Abstract
Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk.
Highlights
Atrial fibrillation (AF) is the most common arrhythmia in humans, characterized by irregularly irregular atrial electrical activity, resulting in asynchronous atrial contraction
We further demonstrated that calcium handling abnormalities, action potential (AP) alterations, and triggered activity are all normalized by knockout of phospholamban, which prevents Tbx5-dependent AF
We previously reported that Tbx5-deficient atrial cardiomyocytes demonstrated AP prolongation and myocardial ectopy
Summary
Atrial fibrillation (AF) is the most common arrhythmia in humans, characterized by irregularly irregular atrial electrical activity, resulting in asynchronous atrial contraction. Ectopic trigger refers to cardiomyocyte ectopy, or initiation of electrical activity at regions outside of the sinoatrial node Both of these cellular phenomena are observed in Tbx adult-specific mutant mice and have been associated with abnormal cellular calcium handling (Dobrev, 2010; Voigt et al, 2012; Voigt et al, 2014; Vest et al, 2005; Shanmugam et al, 2011; Neef et al, 2010; Macquaide et al, 2015; Liang et al, 2008; Lenaerts et al, 2009; Hove-Madsen et al, 2004; Greiser et al, 2011; ElArmouche et al, 2006; Brundel et al, 1999). We further demonstrated that calcium handling abnormalities, AP alterations, and triggered activity are all normalized by knockout of phospholamban, which prevents Tbx5-dependent AF These results establish a direct link between depressed SR Ca2+ sequestration, enhanced NCX activity, and AF. This model suggests that targeting calcium handling pathways may be a treatment approach for a subpopulation of AF patients
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