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RESEARCH ARTICLE Originally Published 26 July 2024

RNA Helicase DDX5 Maintains Cardiac

Function by Regulating CamkIIδ Alternative
Splicing
Kangni Jia, MD, PhD  , Haomai Cheng, MD  , Wenqi Ma, MD, PhD  , Lingfang Zhuang, MD, PhD, Hao Li, MD  , Zhigang Li,

PhD, Ziyang Wang, MD, … SHOW ALL …, and Xiaoxiang Yan, MD, PhD   AUTHOR INFO & AFFILIATIONS

Circulation New online https://doi.org/10.1161/CIRCULATIONAHA.123.064774

   PDF/EPUB

Abstract
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 BACKGROUND: 

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA- 
binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box

helicase 5) is a master regulator of many RNA processes, although its function in
heart physiology remains unclear. 

METHODS: 

We assessed DDX5 expression in human failing hearts and a mouse HF model. 

To study the function of DDX5 in heart, we engineered cardiomyocyte-specific 
Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-
associated virus serotype 9 and performed transverse aortic constriction to ADVERTISEMENT

establish the murine HF model. The mechanisms underlined were subsequently

investigated using immunoprecipitation–mass spectrometry, RNA-sequencing,
alternative splicing analysis, and RNA immunoprecipitation sequencing.

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. We found that DDX5 regulated the aberrant splicing of
Ca2+/calmodulin-dependent protein kinase IIδ (CamkIIδ), thus preventing the
production of CaMKIIδA, which phosphorylates L-type calcium channel by serine
residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we
found increased intracellular Ca2+ transients and increased sarcoplasmic
reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-
associated virus serotype 9 knockdown of CaMKIIδA partially rescued the
cardiac dysfunction and HF in Ddx5 knockout mice.

CONCLUSIONS:

These findings reveal a role for DDX5 in maintaining calcium homeostasis and
cardiac function by regulating alternative splicing in cardiomyocytes, identifying
the DDX5 as a potential target for therapeutic intervention in HF.

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