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| Item Type: | Article |
|---|---|
| Title: | Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy |
| Creators Name: | Hinze, F., Dieterich, C., Radke, M.H., Granzier, H. and Gotthardt, M. |
| Abstract: | 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. KEY MESSAGE: Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction. |
| Keywords: | Heart Failure, Therapy, Mouse Models, RNA Processing, Hypertrophy Signaling, Animals, Mice |
| Source: | Journal of Molecular Medicine |
| ISSN: | 0946-2716 |
| Publisher: | Springer |
| Volume: | 94 |
| Number: | 12 |
| Page Range: | 1349-1358 |
| Date: | December 2016 |
| Official Publication: | https://doi.org/10.1007/s00109-016-1483-3 |
| PubMed: | View item in PubMed |
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