DDX5 maintains cardiac function by regulating CamkII delta alternative splicing

Abstract

Abstract Background Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease. Dead-box protein 5 (DDX5) is a master regulator of many RNA processes, though its functions in heart physiology and disease remain unclear. Purpose To elucidate the function of DDX5 in HF and the mechanisms underlying its role in regulating alternative splicing. Methods and Results We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. Ddx5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. By integrating alternative splicing analysis and RNA immunoprecipitation sequencing data, we identified that DDX5 regulated the aberrant splicing of CamkIIδ, thus preventing the production of CaMKIIδA and maintaining Ca2+ homeostasis. In line with this, we found an increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5 depleted cardiomyocytes. Conclusions Our findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes.