Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure.
Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure.
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DOI：
10.1038/ncomms8229
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发表时间：
2015-06-12
影响因子：
16.6
通讯作者：
Hajjar, Roger J.
中科院分区：
文献类型：
--
作者：
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.
心肌肌浆网钙ATP酶（SERCA 2a）是调节心肌细胞钙循环的关键泵，其活性和表达降低是心力衰竭的标志。我们先前已经描述了小泛素样修饰物1型（SUMO-1）作为SERCA 2a调节剂的作用，并表明SUMO-1在啮齿动物和大型心力衰竭动物模型中的基因转移可恢复心脏功能。在这里，我们确定和表征的小分子，N106，它增加SUMO化的SERCA 2a。该化合物直接激活SUMO激活酶E1连接酶，并触发SERCA 2a的内在SUMO化。我们确定了SUMO E1上的一个口袋可能是N106效应的原因。N106处理增加了培养的大鼠心肌细胞的收缩特性，并显着改善心力衰竭小鼠的心室功能。这种靶向SERCA 2a SUMO化的首个小分子激活剂可作为治疗心力衰竭的潜在治疗策略。 心脏钙泵SERCA 2a的SUMO化影响其活性并促进心肌细胞收缩性。在这里，作者确定了一种小分子N106，它可以增加SERCA 2 SUMO化并改善小鼠的心脏功能，并提出了一种有希望的治疗心力衰竭的治疗策略。
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. SUMOylation of the cardiac calcium pump SERCA2a affects its activity and promotes cardiomyocyte contractility. Here the authors identify a small molecule N106 that increases SERCA2 SUMOylation and improves heart function in mice, and propose a promising therapeutic strategy for treatment of heart failure.
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影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
4.8
作者：
Wang, J;Feng, XH;Schwartz, RJ
通讯作者：
Schwartz, RJ
影响因子：
5.6
作者：
Wang, Yi-Ting;Yang, Wen-Bin;Hung, Jan-Jong
通讯作者：
Hung, Jan-Jong
影响因子：
6
作者：
Jaski, Brian E.;Jessup, Mariell L.;Mancini, Donna M.;Cappola, Thomas P.;Pauly, Daniel F.;Greenberg, Barry;Borow, Kenneth;Dittrich, Howard;Zsebo, Krisztina M.;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.