A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice

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.

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

“…Recent studies investigating the cellular mechanisms of AF have suggested that abnormal atrial calcium handling contributes to AF pathogenesis, leading to trigger formation (56,(58)(59)(60). Although SR calcium content is affected by both SERCA uptake and RYR2-mediated calcium leak, our previous study suggested that Ryr2 binding was not affected in Tbx5 knockout mice, suggesting a primary role of SERCA in TBX5-dependent calcium dysfunction (61). Consistent with this model, increased SERCA activity by reduced PLN, an SERCA inhibitor, rescued the Tbx5-haploinsufficient phenotype ( Figure 5).…”

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

“…Moreover, adult-restricted Tbx5-mutant mice demonstrated spontaneous AF, and in Tbx5-deficient atrial cardiomyocytes, action potential abnormalities occurred due to a decreased SERCA2-mediated sarcoplasmic reticulum calcium uptake (Dai et al, 2019). In human beings, TBX5 is highly expressed in embryonic and postnatal hearts (Hatcher et al, 2000), and a number of TBX5 loss-or gain-of-function mutations have been causally linked to HOS, including CHD and AF as well as cardiac block (Al-Qattan and Abou Al-Shaar, 2015).…”

Mechanisms underlying pro-arrhythmic abnormalities arising from Pitx2-induced electrical remodelling: an in silico intersubject variability study

“…Previous studies have shown that changes in Pitx2 levels lead to electrical remodelling linked to arrhythmogenesis (2) and that Pitx2 regulates membrane effector genes associated with the electrical remodelling in a dose-dependent manner (3,7,8). Therefore, based on the correlation of the Pitx2 levels with remodelled parameters observed in previous studies (3,4,7,8,41) and the correlation of remodelled parameters with changes in APs in the present study, the correlation of the Pitx2 levels with different AF models can be built. In the previous studies, Pitx2 deficiency is associated with the increase in G Na , G up (8) and G CaL (41) and the reduction in G K1 (4).…”

“…Therefore, based on the correlation of the Pitx2 levels with remodelled parameters observed in previous studies (3,4,7,8,41) and the correlation of remodelled parameters with changes in APs in the present study, the correlation of the Pitx2 levels with different AF models can be built. In the previous studies, Pitx2 deficiency is associated with the increase in G Na , G up (8) and G CaL (41) and the reduction in G K1 (4). Interestingly, our simulated results indicated that the incidence of triggered AP was negatively correlated with G Ks and G K1 and was positively correlated with G Na , G CaL and G up .…”

“…Here, we used the AF models (as output) and the corresponding remodelled parameters (as input) to train the artificial neural network (40) to determine the weights of remodelled parameters. Based on the correlation of the Pitx2 levels with remodelled parameters observed in previous studies (3,4,7,8,41) and the correlation of remodelled parameters with changes in APs, the correlation of the Pitx2 levels with different AF models was built.…”