Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy
Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin’s elastic properties can be adjusted phys...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 November 2016
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| In: |
Journal of molecular medicine
Year: 2016, Volume: 94, Issue: 12, Pages: 1349-1358 |
| ISSN: | 1432-1440 |
| DOI: | 10.1007/s00109-016-1483-3 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00109-016-1483-3
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| Author Notes: | Florian Hinze, Christoph Dieterich, Michael H. Radke, Henk Granzier, Michael Gotthardt |
| Summary: | Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin’s elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. |
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| Item Description: | Gesehen am 14.05.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1432-1440 |
| DOI: | 10.1007/s00109-016-1483-3 |