Figure 4. Reduced SERCA function caused by Tbx5 haploinsufficiency is rescued by Gata4 haploinsufficiency in atrial myocytes.

(A–D) Representative SERCA2 traces after steady-state field stimulation at 1 Hz and application of caffeine in the absence of Na_o 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 Tbx5^fl/+;R26^CreERT2 compared with R26^CreERT2 mice and was completely rescued in Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 mice (n = 49 R26^CreERT2, n = 47 Tbx5^fl/+;R26^CreERT2, n = 18 Gata4^fl/+;R26^CreERT2 and n = 30 Gata4^fl/+;Tbx5^fl/+;R26^CreERT2 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 Tbx5^fl/+;R26^CreERT2 compared with R26^CreERT2 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.