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

Changwon Kho; Ahyoung Lee; Dongtak Jeong; Jae Gyun Oh; Przemek A. Gorski; Kenneth Fish; Roberto Sanchez; Robert J. Devita; Geir Christensen; Russell Dahl; Roger J. Hajjar

doi:10.1038/ncomms8229

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

Changwon Kho, Ahyoung Lee, Dongtak Jeong, Jae Gyun Oh, Przemek A. Gorski, Kenneth Fish, Roberto Sanchez, Robert J. Devita, Geir Christensen, Russell Dahl, Roger J. Hajjar

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

Abstract

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.

Original language	English
Article number	7229
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8229
State	Published - 12 Jun 2015

Access to Document

10.1038/ncomms8229

Cite this

@article{6d4b3ac582e04e70ae0c0a42ebc29b4c,

title = "Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure",

abstract = "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.",

author = "Changwon Kho and Ahyoung Lee and Dongtak Jeong and Oh, {Jae Gyun} and Gorski, {Przemek A.} and Kenneth Fish and Roberto Sanchez and Devita, {Robert J.} and Geir Christensen and Russell Dahl and Hajjar, {Roger J.}",

note = "Funding Information: This work was supported by NIH K99 HL116645, R01 HL117505, HL093183, P50 HL112324 and a NHLBI Program of Excellence in Nanotechnology (PEN) Award, contract number HHSN268201000045C.",

year = "2015",

month = jun,

day = "12",

doi = "10.1038/ncomms8229",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure

AU - Kho, Changwon

AU - Lee, Ahyoung

AU - Jeong, Dongtak

AU - Oh, Jae Gyun

AU - Gorski, Przemek A.

AU - Fish, Kenneth

AU - Sanchez, Roberto

AU - Devita, Robert J.

AU - Christensen, Geir

AU - Dahl, Russell

AU - Hajjar, Roger J.

N1 - Funding Information: This work was supported by NIH K99 HL116645, R01 HL117505, HL093183, P50 HL112324 and a NHLBI Program of Excellence in Nanotechnology (PEN) Award, contract number HHSN268201000045C.

PY - 2015/6/12

Y1 - 2015/6/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84931281992&partnerID=8YFLogxK

U2 - 10.1038/ncomms8229

DO - 10.1038/ncomms8229

M3 - Article

C2 - 26068603

AN - SCOPUS:84931281992

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7229

ER -

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

Abstract

Access to Document

Fingerprint

Cite this