Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

Hinze, F.; Dieterich, C.; Radke, M.H.; Granzier, H.; Gotthardt, M.

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

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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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