Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis
Brigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, Ivan P. Moskowitz
Brigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, Ivan P. Moskowitz
View: Text | PDF
Research Article Cardiology Genetics

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

Abstract

Atrial fibrillation (AF), defined by disorganized atrial cardiac rhythm, is the most prevalent cardiac arrhythmia worldwide. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with AF risk, including the cardiogenic transcription factor genes TBX5, GATA4, and NKX2-5. We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data.

Authors

Brigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, Ivan P. Moskowitz

×

Figure 4

Reduced SERCA function caused by Tbx5 haploinsufficiency is rescued by Gata4 haploinsufficiency in atrial myocytes.

Options: View larger image (or click on image) Download as PowerPoint
Reduced SERCA function caused by Tbx5 haploinsufficiency is rescued by G...
(A–D) Representative SERCA2 traces after steady-state field stimulation at 1 Hz and application of caffeine in the absence of Nao provides a measurement of SR load. Removal of caffeine in the absence of external Nao provides a measure of SERCA2-mediated SR calcium uptake. (E) SR load, determined from peak caffeine transients was diminished in Tbx5fl/+;R26CreERT2 compared with R26CreERT2 mice and was completely rescued in Gata4fl/+;Tbx5fl/+;R26CreERT2 mice (n = 49 R26CreERT2, n = 47 Tbx5fl/+;R26CreERT2, n = 18 Gata4fl/+;R26CreERT2 and n = 30 Gata4fl/+;Tbx5fl/+;R26CreERT2 atrial myocytes from 3–5 mice for each genotype). P values were determined by 1-way ANOVA followed by post-hoc Tukey test. (F) SERCA activity determined from the maximal rate of calcium decay was diminished in Tbx5fl/+;R26CreERT2 compared with R26CreERT2 and normalized by Gata4 haploinsufficiency. P values were determined by 1-way ANOVA followed by post-hoc Tukey test. (G) Calcium homeostasis in control atrial myocytes is disrupted by Tbx5 haploinsufficiency and rescued by decreasing Gata4 gene dosage.