A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban
A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban
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DOI：
10.1016/j.ejphar.2017.07.035
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发表时间：
2017-11-05
影响因子：
5
通讯作者：
Nishimoto, Tomoyuki
中科院分区：
文献类型：
--
作者：
Kaneko, Manami;Yamamoto, Hisato;Nishimoto, Tomoyuki
心肌肌/内质网钙依赖的ATPase 2a(SERCA2a)在心肌细胞内的钙转运中起核心作用，并受肌浆网(SR)膜蛋白磷蛋白(PLN)的负性调节。SERCA2a的激活被认为可以改善心力衰竭时的心功能障碍，是一种潜在的治疗心力衰竭的方法。因此，我们开发了一种新的小分子化合物A，并对其进行了体内外表征。化合物A能激活心肌SR囊泡的钙依赖的ATPase活性，但不能激活缺乏PLN的骨骼肌SR囊泡的ATPase活性。表面等离子体共振分析表明，化合物A与PLN之间存在直接的相互作用，表明化合物A与PLN的结合减弱了其对SERCA2a的抑制，导致SERCA2a的激活。SERCA抑制剂thapsigargin抑制化合物A介导的HL-1细胞内钙离子水平的升高，证实了这一点。化合物A还能增加成年大鼠心肌细胞的钙瞬变和收缩与松弛。在离体灌流的大鼠心脏中，化合物A增强了收缩和舒缩功能。此外，静脉滴注化合物A(30 mg/kg)。静脉推注后2 mg/kg/min。输液)显著增强麻醉正常大鼠的舒张期功能。这些结果表明，化合物A是一种新型的SERCA2a激动剂，在体内外均能减弱PLN的抑制作用，增强心脏的收缩和舒缩功能。因此，化合物A可能是一种新的治疗心力衰竭的先导药物。
The cardiac sarco/endoplasmic reticulum Ca2+-dependent ATPase 2a (SERCA2a) plays a central role in Ca2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the Ca2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in Ca2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the Ca2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30 mg/kg, i.v. bolus followed by 2 mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure.