Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure
Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardi...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1283 |
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| author | Mingyao Gu Yuying Zhao Hong Wang Wanwen Cheng Jie Liu Kunfu Ouyang Chaoliang Wei |
| author_facet | Mingyao Gu Yuying Zhao Hong Wang Wanwen Cheng Jie Liu Kunfu Ouyang Chaoliang Wei |
| author_sort | Mingyao Gu |
| collection | DOAJ |
| description | Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardiac function and plays a critical role in the process of heart failure. However, how RBFox2 itself is regulated remains unclear. Here, we dissected transcriptomic signatures, including mRNAs and miRNAs, in a mouse model of heart failure after TAC surgery. A global analysis showed that an asymmetric alternation in gene expression and a large-scale upregulation of miRNAs occurred in heart failure. An association analysis revealed that the latter not only contributed to the degradation of numerous mRNA transcripts, but also suppressed the translation of key proteins such as RBFox2. With the aid of Ago2 CLIP-seq data, luciferase assays verified that RBFox2 was targeted by multiple miRNAs, including Let-7, miR-16, and miR-200b, which were significantly upregulated in heart failure. The overexpression of these miRNAs suppressed the RBFox2 protein and its downstream effects in cardiomyocytes, which was evidenced by the suppressed alternative splicing of the Enah gene and impaired E–C coupling via the repression of the Jph2 protein. The inhibition of Let-7, the most abundant miRNA family targeting RBFox2, could restore the RBFox2 protein as well as its downstream effects in dysfunctional cardiomyocytes induced by ISO treatment. In all, these findings revealed the molecular mechanism leading to RBFox2 depression in heart failure, and provided an approach to rescue RBFox2 through miRNA inhibition for the treatment of heart failure. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:23:02Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-adefa31a142b4a86904e9b6bc41dc3002023-11-30T22:38:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242128310.3390/ijms24021283Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart FailureMingyao Gu0Yuying Zhao1Hong Wang2Wanwen Cheng3Jie Liu4Kunfu Ouyang5Chaoliang Wei6Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Health Science Center, Shenzhen University, Shenzhen 518060, ChinaShenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Health Science Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, ChinaDepartment of Pathophysiology, Health Science Center, Shenzhen University, Shenzhen 518060, ChinaShenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Health Science Center, Shenzhen University, Shenzhen 518060, ChinaDepartment of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, ChinaShenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Health Science Center, Shenzhen University, Shenzhen 518060, ChinaHeart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardiac function and plays a critical role in the process of heart failure. However, how RBFox2 itself is regulated remains unclear. Here, we dissected transcriptomic signatures, including mRNAs and miRNAs, in a mouse model of heart failure after TAC surgery. A global analysis showed that an asymmetric alternation in gene expression and a large-scale upregulation of miRNAs occurred in heart failure. An association analysis revealed that the latter not only contributed to the degradation of numerous mRNA transcripts, but also suppressed the translation of key proteins such as RBFox2. With the aid of Ago2 CLIP-seq data, luciferase assays verified that RBFox2 was targeted by multiple miRNAs, including Let-7, miR-16, and miR-200b, which were significantly upregulated in heart failure. The overexpression of these miRNAs suppressed the RBFox2 protein and its downstream effects in cardiomyocytes, which was evidenced by the suppressed alternative splicing of the Enah gene and impaired E–C coupling via the repression of the Jph2 protein. The inhibition of Let-7, the most abundant miRNA family targeting RBFox2, could restore the RBFox2 protein as well as its downstream effects in dysfunctional cardiomyocytes induced by ISO treatment. In all, these findings revealed the molecular mechanism leading to RBFox2 depression in heart failure, and provided an approach to rescue RBFox2 through miRNA inhibition for the treatment of heart failure.https://www.mdpi.com/1422-0067/24/2/1283RBFox2miRNAsE–C couplingalternative splicingheart failure |
| spellingShingle | Mingyao Gu Yuying Zhao Hong Wang Wanwen Cheng Jie Liu Kunfu Ouyang Chaoliang Wei Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure International Journal of Molecular Sciences RBFox2 miRNAs E–C coupling alternative splicing heart failure |
| title | Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure |
| title_full | Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure |
| title_fullStr | Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure |
| title_full_unstemmed | Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure |
| title_short | Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced Heart Failure |
| title_sort | suppression of rbfox2 by multiple mirnas in pressure overload induced heart failure |
| topic | RBFox2 miRNAs E–C coupling alternative splicing heart failure |
| url | https://www.mdpi.com/1422-0067/24/2/1283 |
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