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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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Hauptverfasser: Hinze, Florian (Verfasst von) , Dieterich, Christoph (Verfasst von) , Radke, Michael H. (Verfasst von) , Granzier, Henk (Verfasst von) , Gotthardt, Michael (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 26 November 2016
In: Journal of molecular medicine
Year: 2016, Jahrgang: 94, Heft: 12, Pages: 1349-1358
ISSN:1432-1440
DOI:10.1007/s00109-016-1483-3
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00109-016-1483-3
Volltext
Verfasserangaben:Florian Hinze, Christoph Dieterich, Michael H. Radke, Henk Granzier, Michael Gotthardt
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 14.05.2020
Beschreibung:Online Resource
ISSN:1432-1440
DOI:10.1007/s00109-016-1483-3

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