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Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure

Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of S...

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Autores principales: Kho, Changwon, Lee, Ahyoung, Jeong, Dongtak, Oh, Jae Gyun, Gorski, Przemek A., Fish, Kenneth, Sanchez, Roberto, DeVita, Robert J., Christensen, Geir, Dahl, Russell, Hajjar, Roger J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467461/
https://www.ncbi.nlm.nih.gov/pubmed/26068603
http://dx.doi.org/10.1038/ncomms8229
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author Kho, Changwon
Lee, Ahyoung
Jeong, Dongtak
Oh, Jae Gyun
Gorski, Przemek A.
Fish, Kenneth
Sanchez, Roberto
DeVita, Robert J.
Christensen, Geir
Dahl, Russell
Hajjar, Roger J.
author_facet Kho, Changwon
Lee, Ahyoung
Jeong, Dongtak
Oh, Jae Gyun
Gorski, Przemek A.
Fish, Kenneth
Sanchez, Roberto
DeVita, Robert J.
Christensen, Geir
Dahl, Russell
Hajjar, Roger J.
author_sort Kho, Changwon
collection PubMed
description Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identify a pocket on SUMO E1 likely to be responsible for N106's effect. N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure. This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure.
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spelling pubmed-44674612015-07-13 Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure Kho, Changwon Lee, Ahyoung Jeong, Dongtak Oh, Jae Gyun Gorski, Przemek A. Fish, Kenneth Sanchez, Roberto DeVita, Robert J. Christensen, Geir Dahl, Russell Hajjar, Roger J. Nat Commun Article Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identify a pocket on SUMO E1 likely to be responsible for N106's effect. N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure. This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure. Nature Pub. Group 2015-06-12 /pmc/articles/PMC4467461/ /pubmed/26068603 http://dx.doi.org/10.1038/ncomms8229 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kho, Changwon
Lee, Ahyoung
Jeong, Dongtak
Oh, Jae Gyun
Gorski, Przemek A.
Fish, Kenneth
Sanchez, Roberto
DeVita, Robert J.
Christensen, Geir
Dahl, Russell
Hajjar, Roger J.
Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title_full Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title_fullStr Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title_full_unstemmed Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title_short Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
title_sort small-molecule activation of serca2a sumoylation for the treatment of heart failure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467461/
https://www.ncbi.nlm.nih.gov/pubmed/26068603
http://dx.doi.org/10.1038/ncomms8229
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