EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments.
EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments.
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DOI：
10.3390/ijms232314517
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发表时间：
2022-11-22
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
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足够的心肌收缩力对于确保充足的心输出量以提供足够的终末器官灌注是必要的。心输出量不足以及因心肌收缩力降低导致的重要器官灌注减少是心力衰竭终末期的一个标志。目前没有可直接作用于收缩蛋白以提高心肌收缩力并降低死亡率的治疗方法。本研究的目的是提出一个概念验证，以帮助开发用于增强临床心力衰竭患者心肌收缩力的肌肉激活剂（促肌药物）。在此，我们结合心肌细胞力学、ATP转换的生化定量以及对通透化猪心肌的小角度X射线衍射，来研究EMD - 57033（EMD）激活肌球蛋白的机制。我们表明，在亚最大和收缩期钙浓度下，EMD可增加猪心肌的收缩力。生化检测显示，在舒张条件下，EMD降低了处于节能超松弛（SRX）状态的肌球蛋白头部的比例，这些肌球蛋白头部在收缩过程中不太可能与肌动蛋白相互作用。结构检测显示，EMD使舒张肌肉中的肌球蛋白头部从靠近粗肌丝主干的结构有序状态转变为更靠近肌动蛋白丝的无序状态，同时诱导肌动蛋白丝上的肌钙蛋白复合物发生结构变化。EMD对激活肌球蛋白头部和肌钙蛋白复合物的双重作用为使用小分子肌肉激活剂增强心力衰竭患者的心肌收缩力提供了概念验证。
Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure.
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影响因子：
3.4
作者：
Ma W;Gong H;Jani V;Lee KH;Landim-Vieira M;Papadaki M;Pinto JR;Aslam MI;Cammarato A;Irving T
通讯作者：
Irving T
DOI：
10.1073/pnas.1809540115
发表时间：
2018-08-28
影响因子：
11.1
作者：
Anderson, Robert L.;Trivedi, Darshan V.;Spudich, James A.
通讯作者：
Spudich, James A.
影响因子：
2.9
作者：
Li, MX;Spyracopoulos, L;Sykes, BD
通讯作者：
Sykes, BD
影响因子：
3.4
作者：
Ma, Weikang;Gong, Henry;Irving, Thomas
通讯作者：
Irving, Thomas
影响因子：
7.3
作者：
de Zeeuw, S;Trines, SAIP;Duncker, DJ
通讯作者：
Duncker, DJ