Cardiovascular research · 2025
Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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He Mengying, Tay Woan Ting, Song Ningjing, Liu Tian, Ren Shuxun Vincent, Zhu Cansheng, Onubogu Nkechi, Biler Ozgu, Tan Jia En, Keezer Caitlin, He Xingyu, Pham Anthony, Sheng Shuyuan, Ding Hao, Lin Junxin, Wang Lingjun, Wang Yigang, Hu Xinyang, Wang Yibin, Gao Chen
Аннотация
AIMS: Alternative mRNA splicing is a significant part of transcriptome reprogramming during the pathological manifestation of heart diseases. Earlier studies have identified a muscle-specific isoform of RBFox1 (RNA binding fox-1 homolog 1) to be a key RNA splicing regulator in pressure overload induced heart failure. However, the physiological impact of RBFox1 in myocardial infarction (MI), and the downstream mRNA alternative splicing events during MI induced cardiac remodelling remains unknown.
METHODS AND RESULTS: Here we found RBFox1 expression was significantly decreased in Sprague-Dawley rat hearts post MI. Restoring the expression of RBFox1 prevented cardiac remodelling and dysfunction post MI characterized by improved cardiac function, reduced hypertrophy and fibrosis, associated with attenuated induction of cardiac stress marker genes. In cultured cardiomyocytes, expression of RBFox1 was sufficient to prevent hypoxia induced cell death measured by TUNEL staining and cleaved caspase 3, while inactivation of RBFox1 aggravated cardiac cell death. Mechanistically, we identified RBFox1 expression affected a broad spectrum of gene expression in post-MI hearts. In addition, a hypoxia-sensitive alternative splicing variant of Mbnl1 (Muscleblind-like 1) mRNA was identified to be regulated by RBFox1, resulting in the expression of a cell death related Mbnl1 isoform with 12 amino-acid deletion at the C-terminus (Mbnl1-ΔExon7). Strikingly, the selective inhibition of Mbnl1 Exon7 inclusion using anti-sense oligo protected the heart from myocardial infarction induced injury in vivo.
CONCLUSION: In summary, we have established a cardio-protective role of RBFox1 in myocardial infarction induced cardiac remodelling and dysfunction. Restoration of RBFox1 expression, and targeted modulation of its downstream alternative splicing target Mbnl1, is a potential therapeutic approach for cardiac dysfunction and remodelling in MI injured heart.
METHODS AND RESULTS: Here we found RBFox1 expression was significantly decreased in Sprague-Dawley rat hearts post MI. Restoring the expression of RBFox1 prevented cardiac remodelling and dysfunction post MI characterized by improved cardiac function, reduced hypertrophy and fibrosis, associated with attenuated induction of cardiac stress marker genes. In cultured cardiomyocytes, expression of RBFox1 was sufficient to prevent hypoxia induced cell death measured by TUNEL staining and cleaved caspase 3, while inactivation of RBFox1 aggravated cardiac cell death. Mechanistically, we identified RBFox1 expression affected a broad spectrum of gene expression in post-MI hearts. In addition, a hypoxia-sensitive alternative splicing variant of Mbnl1 (Muscleblind-like 1) mRNA was identified to be regulated by RBFox1, resulting in the expression of a cell death related Mbnl1 isoform with 12 amino-acid deletion at the C-terminus (Mbnl1-ΔExon7). Strikingly, the selective inhibition of Mbnl1 Exon7 inclusion using anti-sense oligo protected the heart from myocardial infarction induced injury in vivo.
CONCLUSION: In summary, we have established a cardio-protective role of RBFox1 in myocardial infarction induced cardiac remodelling and dysfunction. Restoration of RBFox1 expression, and targeted modulation of its downstream alternative splicing target Mbnl1, is a potential therapeutic approach for cardiac dysfunction and remodelling in MI injured heart.