cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation.
cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation.
复制标题
CMyBPC的磷酸化调节奥美卡比对心肌力产生的影响。
DOI：
10.1085/jgp.202012816
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Stelzer JE
中科院分区：
文献类型：
--
作者：
Mamidi R;Holmes JB;Doh CY;Dominic KL;Madugula N;Stelzer JE
Mamidi et al.研究了心肌肌球蛋白结合蛋白C（cMyBPC）磷酸化对Omecamtiv Mecarbil（OM）（一种候选心力衰竭治疗）应答的影响。他们表明，OM将心肌力动力学与cMyBPC磷酸化解偶联，这表明了重要的治疗限制。Omecamtiv Mecarbil（OM）是一种直接肌球蛋白运动激活剂，目前正在测试作为心力衰竭（HF）患者中常规正性肌力药物的治疗替代品。已知HF患者表现出β-肾上腺素能信号传导失调和心肌肌球蛋白结合蛋白C（cMyBPC）磷酸化降低，这是心肌力产生的关键调节剂。然而，OM在改变cMyBPC磷酸化条件下的功能效应尚未确定。在这里，我们测试了OM对力产生和交叉桥（XB）动力学的影响，使用从野生型（WT）心脏和从心脏中分离的小鼠心肌制备物表达S273 A，S282 A和S302 A取代（SA）的M结构域，cMyBPC的C1和C2结构域之间，不能磷酸化。在次最大Ca 2+激活，OM介导的力增强不太明显，SA比WT心肌准备。此外，SA心肌制备物缺乏在WT心肌制备物中观察到的力的剂量依赖性增加。OM孵育后，WT和SA心肌制备物之间XB脱离率（krel）的基础差异被消除，表明当cMyBPC磷酸化降低时，OM对XB行为的影响不同。同样，在用蛋白激酶A磷酸化cMyBPC的心肌制备物中，与OM孵育显著减慢WT和SA心肌制备物中的krel。总的来说，我们的数据表明OM和XB行为的影响之间存在强烈的相互作用，因此它有效地将肌节与cMyBPC磷酸化水平解偶联。我们的研究结果表明，OM可能会显着改变在体心脏对β-肾上腺素能刺激的反应。
Mamidi et al. investigate the effect of cardiac myosin-binding protein C (cMyBPC) phosphorylation on the response to omecamtiv mecarbil (OM), a candidate heart failure therapy. They show that OM uncouples myocardial force dynamics from cMyBPC phosphorylation, suggesting important therapeutic constraints. Omecamtiv mecarbil (OM), a direct myosin motor activator, is currently being tested as a therapeutic replacement for conventional inotropes in heart failure (HF) patients. It is known that HF patients exhibit dysregulated β-adrenergic signaling and decreased cardiac myosin-binding protein C (cMyBPC) phosphorylation, a critical modulator of myocardial force generation. However, the functional effects of OM in conditions of altered cMyBPC phosphorylation have not been established. Here, we tested the effects of OM on force generation and cross-bridge (XB) kinetics using murine myocardial preparations isolated from wild-type (WT) hearts and from hearts expressing S273A, S282A, and S302A substitutions (SA) in the M domain, between the C1 and C2 domains of cMyBPC, which cannot be phosphorylated. At submaximal Ca2+ activations, OM-mediated force enhancements were less pronounced in SA than in WT myocardial preparations. Additionally, SA myocardial preparations lacked the dose-dependent increases in force that were observed in WT myocardial preparations. Following OM incubation, the basal differences in the rate of XB detachment (krel) between WT and SA myocardial preparations were abolished, suggesting that OM differentially affects the XB behavior when cMyBPC phosphorylation is reduced. Similarly, in myocardial preparations pretreated with protein kinase A to phosphorylate cMyBPC, incubation with OM significantly slowed krel in both the WT and SA myocardial preparations. Collectively, our data suggest there is a strong interplay between the effects of OM and XB behavior, such that it effectively uncouples the sarcomere from cMyBPC phosphorylation levels. Our findings imply that OM may significantly alter the in vivo cardiac response to β-adrenergic stimulation.
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5.6
作者：
Gruen, M;Gautel, M
通讯作者：
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DOI：
10.1016/j.bbadis.2019.01.007
发表时间：
2019-03-01
影响因子：
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