ArticlePloS one2018
Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- RNA splicing and cardiovascular disease: a guide for cardiologists.European heart journal · 2026Review
- High-throughput sensitive screening of small molecule modulators of microexon alternative splicing using dual Nano and Firefly luciferase reporters.Nature communications · 2024Article
- [Research progress on the expression of theZhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2023Review
- Cardiac splicing as a diagnostic and therapeutic target.Nature reviews. Cardiology · 2023Review
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- HDAC6 modulates myofibril stiffness and diastolic function of the heart.The Journal of clinical investigation · 2022Article
- SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy.Genomics, proteomics & bioinformatics · 2022Article
- RBM20, a Therapeutic Target to Alleviate Myocardial StiffnessFrontiers in cardiovascular medicine · 2022Review
- The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles.Biophysical reviews · 2021Review
- RBM20-Related Cardiomyopathy: Current Understanding and Future Options.Journal of clinical medicine · 2021Review
- The Sarcomeric Spring Protein Titin: Biophysical Properties, Molecular Mechanisms, and Genetic Mutations Associated with Heart Failure and Cardiomyopathy.Current cardiology reports · 2021Review
- Article
- New Insights in RBM20 Cardiomyopathy.Current heart failure reports · 2020Review
- iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy.Cell reports · 2020Article
- Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure.Journal of clinical medicine · 2020Review
- Review
- Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance.The Journal of general physiology · 2019Article
- Alternative Splicing Regulator RBM20 and Cardiomyopathy.Frontiers in molecular biosciences · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Diastolic dysfunction is increasingly prevalent in our ageing society and an important contributor to heart failure. The giant protein titin could serve as a therapeutic target, as its elastic properties are a main determinant of cardiac filling in diastole. This study aimed to develop a high throughput pharmacological screen to identify small molecules that affect titin isoform expression through differential inclusion of exons encoding the elastic PEVK domains. We used a dual luciferase splice reporter assay that builds on the titin splice factor RBM20 to screen ~34,000 small molecules and identified several compounds that inhibit the exclusion of PEVK exons. These compounds belong to the class of cardenolides and affect RBM20 dependent titin exon exclusion but did not affect RBFOX1 mediated splicing of FMNL3. We provide evidence that cardenolides do not bind to the RNA interacting domain of RBM20, but reduce RBM20 protein levels and alter transcription of select splicing factors that interact with RBM20. Cardenolides affect titin isoform expression. Understanding their mode of action and harnessing the splice effects through chemical modifications that suppress the effects on ion homeostasis and more selectively affect cardiac splicing has the potential to improve cardiac filling and thus help patients with diastolic heart failure, for which currently no targeted therapy exists.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.