부산대학교 도서관

Introduction: Genetic predisposition plays a profound impact on the incidence of atrial fibrillation (AF). GWAS and family studies have identified a number of genes with increased risk of AF, including the T-box transcription factor gene TBX5. Adult-specific deletion of Tbx5 (TBX5fl/fl;R26CreERT2) leads to spontaneous and sustained AF, which is characterized by prolonged action potentials (APs) and spontaneous depolarizations as well as increased propensity for triggered activity, both of which could be normalized by heavy cytosolic Ca2+ buffering. Hypothesis: Electrophysiological abnormalities and triggered activity are secondary to abnormal Ca2+ handling. Methods and Results: We aimed to define the mechanism of AP prolongation and triggered activity in Tbx5 -deleted adult mice. First we examined proteins important to Ca2+ handling, including L-type Ca2+ channels, ryanodine receptor (RYR2), SR Ca2+ ATPase (SERCA), Na+-Ca2+ exchanger (NCX), and phospholamban (PLN). We show that while RYR2 expression was TBX5-dependent, expression of L-type Ca2+channel remained normal. Additionally, SERCA expression was decreased and PLN expression was increased, resulting reduce SR Ca2+ load and reduced SERCA mediated Ca2+ uptake in Tbx5 knockout mice (24 ± 8% and 31 ± 9% respectively). In contrast to SR Ca2+ uptake, NCX expression was increased, resulting in 38 ± 18% increase in NCX mediated Ca2+ efflux, which can explain AP prolongation and a propensity for triggered activity. Next we investigated the effects of dose-dependent decrease of Pln , on the Tbx5 knockout mouse. Consistent with the importance of the TBX5-SERCA-PLN axis, we observed dose dependent rescue of SR load, SERCA activity and AF susceptibility in Tbx5fl/fl;Pln+/-;R26CreERT2 or Tbx5fl/fl;Pln-/-;R26CreERT2 mice. Conclusions: Loss of Tbx5 leads to a decrease in the role of the SR in cellular Ca2+ handling with countervailing Ca2+ extrusion via INCX,which provides a molecular mechanism for the AP prolongation and may account for triggered activity. These findings suggest a mechanism of abnormal Ca2+ handling in Tbx5 knockout model of AF that has potential clinical implications for understanding trigger formation and for designing novel therapies to treat AF. [ABSTRACT FROM AUTHOR]