Research Article: Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling

Date Published: June 11, 2018

Publisher: Public Library of Science

Author(s): Martin Liss, Michael H. Radke, Jamina Eckhard, Martin Neuenschwander, Vita Dauksaite, Jens-Peter von Kries, Michael Gotthardt, Ravindra N. Singh.

http://doi.org/10.1371/journal.pone.0198492

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.

Partial Text

In developed countries heart failure (HF) keeps the top spot in mortality statistics and although prevention and therapy have continuously been improved over the past 30 years, the prevalence of heart failure remains high [1]. Multiple environmental and genetic factors contribute to the development of heart failure. This includes age, sex, diabetes, kidney disease, inflammation, and mutations in sarcomeric proteins such as titin and splice factors such as RBM20, a regulator of titin based stiffness [2]. The classification into systolic versus diastolic heart failure relates to the underlying pathophysiology with reduced ejection fraction in systole (HFrEF) or inefficient filling of the ventricle in diastole with preserved ejection fraction (HFpEF), respectively [3]. Half of all patients with HF belong to the latter group, which is heterogeneous and poorly characterized [4].

Diastolic heart failure is notoriously difficult to treat with little or no benefit from classical heart failure medication such as ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, or beta-blockers [23–25]. Thus, AHA/ACC guidelines focus on risk factors such as hypertension, arrhythmia, increased venous pressure, myocardial ischemia, diabetes and lack of physical fitness, rather than causal treatment [26,27].

 

Source:

http://doi.org/10.1371/journal.pone.0198492

 

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