期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 94, 期 12, 页码 1349-1358出版社
SPRINGER
DOI: 10.1007/s00109-016-1483-3
关键词
Heart failure; Therapy; Mouse models; RNA processing; Hypertrophy signaling
资金
- Deutsche Forschungsgemeinschaft, Bonn, Germany
- European Research Council [StG282078]
- Bundesministerium fur Bildung und Forschung, Berlin, Germany (CaRNAtion)
- NIH [R01HL062881]
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 similar to 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. 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.
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