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.
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Przemek A
authors.initials: PA
authors.lastname: Gorski
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fish
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sanchez
authors.affiliation: 1] Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Department of Pharmacology and System Therapeutics, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo 0450, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Department of Pharmaceutical Science, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.affiliation: Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D058207:Sumoylation
chemical_list: C506948:Atp2a2 protein, rat; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse