Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

• Verfasst von: Hinze, Florian [VerfasserIn]
• Verfasst von: Dieterich, Christoph [VerfasserIn]
• Verfasst von: Radke, Michael H. [VerfasserIn]
• Verfasst von: Granzier, Henk [VerfasserIn]
• Verfasst von: Gotthardt, Michael [VerfasserIn]
• Titel: Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy
• Verf.angabe: Florian Hinze, Christoph Dieterich, Michael H. Radke, Henk Granzier, Michael Gotthardt
• E-Jahr: 2016
• Jahr: 26 November 2016
• Umfang: 10 S.
• Fussnoten: Gesehen am 14.05.2020
• Titel Quelle: Enthalten in: Journal of molecular medicine
• Ort Quelle: Berlin : Springer, 1922
• Jahr Quelle: 2016
• Band/Heft Quelle: 94(2016), 12, Seite 1349-1358
• ISSN Quelle: 1432-1440
• DOI: doi:10.1007/s00109-016-1483-3
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1698232268

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.