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Rbfox1 Regulates Calcium Signaling to Prevent Pressure Overload Induced Cardiac Dysfunction
Author(s) -
Umar Sadiq,
Zhu Wuqiang,
Bender Ingrid,
Van Berlo Jop
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1069.2
Subject(s) - rna splicing , biology , alternative splicing , rna binding protein , microbiology and biotechnology , pressure overload , splicing factor , rna , muscle hypertrophy , gene , cancer research , endocrinology , messenger rna , genetics , cardiac hypertrophy
RNA splicing and processing provide important means of genetic control to diversify gene function, and fine‐tune protein production. RNA regulation is a critical step in the expression of most genes, and its misregulation often results in human disease. Rbfox1 is a RNA binding protein that regulates alternative splicing and RNA stability, and plays an important role in regulating alternative splicing (AS) in neurons, skeletal muscle, and the heart. Recently, Rbfox1 was identified as a critical regulator of Mef2 splicing to protect the heart from failure. However, its role in protecting the heart from failing is likely not limited to Mef2 splicing. To begin to study the role of Rbfox1 in heart failure, we generated cardiomyocyte specific Rbfox1 gene‐deletion mice (cRbfox1−/−). Cardiomyocyte specific deletion of Rbfox1 was confirmed by Western blotting and immunohistochemistry. cRbfox1−/− mice showed mild hypertrophy and depressed cardiac function under homeostatic conditions, which did not deteriorate with age. Pressure overload by trans‐aortic constriction (TAC) caused exaggerated cardiac hypertrophy and accelerated heart failure in cRbfox1−/− compared to wildtype mice. Since Rbfox1 is a known RNA binding protein, we performed RNA sequencing and found significant changes in calcium regulated genes. We measured calcium dynamics and noted a significantly delayed Calcium reuptake into the Sarcoplasmic Reticulum, which is likely caused by decreased SERCA2a expression on Western blot. In conclusion, Rbfox1 is important to maintain cardiac function by regulating calcium signaling. We are currently unraveling the mechanisms via which Rbfox1 regulates Serca2a function. Support or Funding Information Acknowledgement: This work was supported by National Institutes of Health grants and Lillehei Scholar Award (to JVB).