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RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure
Chen Gao, … , Jau-Nian Chen, Yibin Wang
Chen Gao, … , Jau-Nian Chen, Yibin Wang
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):195-206. https://doi.org/10.1172/JCI84015.
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Research Article Cardiology Article has an altmetric score of 4

RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

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Abstract

RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload–induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease.

Authors

Chen Gao, Shuxun Ren, Jae-Hyung Lee, Jinsong Qiu, Douglas J. Chapski, Christoph D. Rau, Yu Zhou, Maha Abdellatif, Astushi Nakano, Thomas M. Vondriska, Xinshu Xiao, Xiang-Dong Fu, Jau-Nian Chen, Yibin Wang

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Figure 7

Restoring RBFox1 prevented pathological hypertrophy in pressure-overloaded mouse hearts.

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Restoring RBFox1 prevented pathological hypertrophy in pressure-overload...
(A) Western blot analysis of RBFox1 protein in wild-type or single-transgenic hearts (Non-TG) compared with double-transgenic hearts (RBFox1-TG) 6 weeks following sham or TAC operation. (B) Quantification of Mef2 α1/α2 transcript ratio in non-TG and RBFox1-TG hearts after 2 weeks of doxycycline induction (n = 3 each sample). *P < 0.05. (C) Heart weight (HW) and body weight ratios in sham-operated mice and non-TG (NTG) and RBFox1-TG mice 6 weeks after TAC (Sham-NTG, n = 9; Sham-RBFox1-TG, n = 9; TAC-NTG, n = 15; TAC-RBFox1-TG, n = 16). *P < 0.05, **P < 0.01. (D) Cross-sectional area of cardiomyocytes in sham-operated mice and non-TG or RBFox1-TG mice after TAC. Average values were derived from 100 myocytes of from each group. **P < 0.05. (E) Ejection fraction of sham- and TAC-operated non-TG and RBFox1-TG mice measured by echocardiography up to 5 weeks after TAC (Sham-NTG, n = 9; Sham-RBFox1-TG, n = 9; TAC-NTG, n = 15; TAC-RBFox1-TG, n = 16). **P < 0.05, TAC-NTG vs. TAC-RBFox1-TG. #P < 0.05, Sham-NTG vs. TAC-NTG. (F) Anf and Bnp mRNA expression levels in non-TG and RBFox1-TG mice following sham surgery or 5 weeks after TAC (n = 3 each group). *P < 0.05. (G) Representative images of Masson trichrome–stained ventricular sections from the sham- and TAC-operated non-TG and RBFox1-TG mice as indicated. Original magnification, ×20. Data are representative of at least 3 independent experiments. Significant differences between groups were determined by Student’s t test (B) or multiway ANOVA (C–F).

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