Abstract
Ca2+ is critical for cardiac electrical conduction and contractility, and aberrant Ca2+ homeostasis causes arrhythmia and heart failure. Chromatin remodeling modulates gene expression involved in cardiac sarcomere assembly and postnatal heart function. However, the chromatin-remodeling regulatory mechanism of cardiac Ca2+ homeostasis is unknown. Here, we found that Znhit1, a core subunit of the SRCAP remodeling complex, was essential for heart function. Deletion of Znhit1 in postnatal hearts of mice resulted in arrhythmia, idiopathic vacuolar cardiomyopathy, rapid heart failure, and premature sudden death. In addition, the level of Casq1, a sarcoplasmic reticulum Ca2+ regulatory protein, was massively elevated while SERCA2a showed reduced protein level. Mechanistically, the Znhit1 modulated the expression of Casq1 and SERCA2a by depositing H2A.Z at their promoters. Deletion of Casq1 could substantially alleviate the vacuolar formation in Znhit1 Casq1 KO mice. These findings demonstrate that Znhit1 is required for postnatal heart function and maintains cardiac Ca2+ homeostasis and that accumulation of Casq1 might be a causative factor for vacuolar cardiomyopathy.
Highlights
Ca2+ is critical for cardiac electrical conduction and contraction [1, 2]
To understand the function of the SRCAP chromatin-remodeling complex in the postnatal heart, we deleted zinc finger HIT-domain–containing protein 1 (Znhit1) in postnatal cardiomyocytes by breeding Znhit1 floxed (Znhit1fl/fl) mice with Myh6-Cre mice [20, 21] to generate Znhit1fl/fl; Myh6-Cre mice
The efficiency of Znhit1 deletion was determined by quantitative realtime PCR and Western blotting using heart tissues from mice on P10 (Supplemental Figure 1, A–C)
Summary
Ca2+ is critical for cardiac electrical conduction and contraction [1, 2]. While excitation-contraction coupling triggers Ca2+ release from the sarcoplasmic reticulum (SR) to cytoplasm via ryanodine receptors (RyRs), uptake of Ca2+ back to the SR is largely accomplished by SR Ca2+-ATPase 2a (SERCA2a) [2, 3]. Casq is highly homologous to Casq and these 2 proteins function to regulate Ca2+ homeostasis in muscle cells [5]. Both Casq and Casq are present in skeletal muscles, only Casq is found in cardiomyocytes. Transgenic mice with Casq overexpression in cardiomyocytes had severe dilated cardiomyopathy and died prematurely by age 16 weeks [6, 7]
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