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

Author

Listed:
  • Changwon Kho

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Ahyoung Lee

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Dongtak Jeong

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Jae Gyun Oh

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Przemek A. Gorski

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Kenneth Fish

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

  • Roberto Sanchez

    (Icahn School of Medicine at Mount Sinai)

  • Robert J. DeVita

    (Icahn School of Medicine at Mount Sinai
    Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai)

  • Geir Christensen

    (Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo)

  • Russell Dahl

    (Rosalind Franklin University of Medicine and Science)

  • Roger J. Hajjar

    (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)

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.

Suggested Citation

  • 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, 2015. "Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8229
    DOI: 10.1038/ncomms8229
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    Cited by:

    1. Sangsang Zhu & Chao Quan & Ruizhen Wang & Derong Liang & Shu Su & Ping Rong & Kun Zhou & Xinyu Yang & Qiaoli Chen & Min Li & Qian Du & Jingzi Zhang & Lei Fang & Hong-Yu Wang & Shuai Chen, 2022. "The RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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