| First Author | Hinze F | Year | 2016 |
| Journal | J Mol Med (Berl) | Volume | 94 |
| Issue | 12 | Pages | 1349-1358 |
| PubMed ID | 27889803 | Mgi Jnum | J:237828 |
| Mgi Id | MGI:5817048 | Doi | 10.1007/s00109-016-1483-3 |
| Citation | Hinze F, et al. (2016) Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy. J Mol Med (Berl) 94(12):1349-1358 |
| abstractText | 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. |
