GSE60538
Sox5 and Sox6 direct a cardiac adaptive response to pressure overload
Rationale: We previously demonstrated that the transcription factor Sox6 regulates skeletal muscle biology by determining myofiber composition and muscle performance. Although the role of Sox6 and Sox5, its closest paralog, has not been ascertained in the heart, genome-wide association studies linked both Sox5 and Sox6 to cardiovascular disease. Objective: This study identifies the role of Sox5 and Sox6 in the adult mammalian heart under normal and stress conditions. Methods and Results: Using Sox5 and Sox6 cardiac-specific and Sox5 conduction system-specific knockout mice, we investigated the role of the two transcription factors in the heart under normal conditions and during cardiac stress. Sox5/6-deficient (DKO) mice displayed blunted cardiac contractility, which was present in Sox5 but not Sox6 single KO mice. DKO mice had a mild reduction in blood pressure, and conduction-specific knockout of Sox5 resulted in a reduced heart rate at baseline. After cardiac pressure overload, DKO mice showed increased lethality compared to control mice and were more prone to develop heart failure. We performed RNA deep sequencing in ventricles from DKO and control mice to identify potential Sox5/6 target genes and found altered expression of genes encoding regulators of calcium handling and cation transporters. Patch-clamping in isolated cardiomyocytes revealed shortened action potential duration in Sox5 KO cells. Conclusions: Unlike in skeletal muscle, our results suggest Sox5 but not Sox6 to be a major regulator of cardiac function and rhythm. Sox5 is essential to preserve cardiac function under normal conditions by maintaining contractility and to prevent cardiac failure after pressure overload. Overall design: Examination of 4 cardiac ventricles per genotype (DKO and control).