The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy.
| Autor: | Makarewich CA; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Munir AZ; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Schiattarella GG; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Bezprozvannaya S; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Raguimova ON; Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States., Cho EE; Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States., Vidal AH; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Robia SL; Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, United States., Bassel-Duby R; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States., Olson EN; Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2018 Oct 09; Vol. 7. Date of Electronic Publication: 2018 Oct 09. |
| DOI: | 10.7554/eLife.38319 |
| Abstrakt: | Calcium (Ca 2+ ) dysregulation is a hallmark of heart failure and is characterized by impaired Ca 2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca 2+ -ATPase (SERCA). We recently discovered a micropeptide named DWORF ( DW arf O pen R eading F rame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca 2+ dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic. Competing Interests: CM CAM has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706), AM, GS, SB, OR, EC, AV, SR No competing interests declared, RB RB-D has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706), EO ENO has filed a provisional patent application to use DWORF for treatment of heart failure (Application #62/324,706) (© 2018, Makarewich et al.) |
| Databáze: | MEDLINE |
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