Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor.
Improvement of cardiomyocyte function by a novel pyrimidine-based CaMKII-inhibitor.
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DOI：
10.1016/j.yjmcc.2017.12.015
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发表时间：
2018-03
影响因子：
5
通讯作者：
Maier LS
中科院分区：
文献类型：
--
作者：
Neef S;Steffens A;Pellicena P;Mustroph J;Lebek S;Ort KR;Schulman H;Maier LS
Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）的病理性活性增加和相关的肌浆网Ca 2+泄漏被认为是心力衰竭和心律失常的重要新药物靶点。然而，用于治疗用途的CaMKII抑制化合物仍然缺乏。我们现在报告的细胞和分子的影响，一种新的嘧啶为基础的CaMKII抑制剂开发的临床应用。我们的研究结果表明，AS 105是一种高亲和力的ATP竞争性CaMKII抑制剂，通过其作用模式，它对自磷酸化CaMKII也有效（与常用的变构CaMKII抑制剂KN-93相反）。在来自人类供体的分离心房心肌细胞和来自CaMK II δ C过表达心力衰竭小鼠的心室肌细胞中，通过Ca 2+火花或[Ca 2 +]i的丁卡因敏感性变化测量，AS 105可有效降低舒张期SR Ca 2+渗漏38%至65%。与此一致，我们发现AS 105抑制了致炎性自发心肌细胞Ca 2+释放（53%）。此外，SR积累Ca 2+的能力被AS 105增强，如小鼠细胞中Ca 2+瞬时振幅的静息后增强和SR Ca 2+含量增加所示。因此，这些细胞在基础刺激期间具有改善的收缩期Ca 2+瞬时振幅和收缩性。重要的是，CaMKII抑制不损害收缩期部分Ca 2+释放，舒张期SR Ca 2+再摄取通过SERCA 2a或Ca 2+挤出通过NCX。AS 105是一种新型的高效ATP竞争性CaMKII抑制剂。在体外，它有效地减少SR Ca 2 +-泄漏，从而改善SR Ca 2 +-积累和减少细胞促炎相关性，而不会对兴奋-收缩偶联产生负面影响。这些发现进一步验证了CaMKII作为心血管疾病的关键靶点，涉及遗传，变构抑制剂和假底物抑制剂。
Pathologically increased activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the associated Ca2+-leak from the sarcoplasmic reticulum are recognized to be important novel pharmacotherapeutic targets in heart failure and cardiac arrhythmias. However, CaMKII-inhibitory compounds for therapeutic use are still lacking. We now report on the cellular and molecular effects of a novel pyrimidine-based CaMKII inhibitor developed towards clinical use. Our findings demonstrate that AS105 is a high-affinity ATP-competitive CaMKII-inhibitor that by its mode of action is also effective against autophosphorylated CaMKII (in contrast to the commonly used allosteric CaMKII-inhibitor KN-93). In isolated atrial cardiomyocytes from human donors and ventricular myocytes from CaMKIIδC-overexpressing mice with heart failure, AS105 effectively reduced diastolic SR Ca2+ leak by 38% to 65% as measured by Ca2+-sparks or tetracaine-sensitive shift in [Ca2+]i. Consistent with this, we found that AS105 suppressed arrhythmogenic spontaneous cardiomyocyte Ca2+-release (by 53%). Also, the ability of the SR to accumulate Ca2+ was enhanced by AS105, as indicated by improved post-rest potentiation of Ca2+-transient amplitudes and increased SR Ca2+-content in the murine cells. Accordingly, these cells had improved systolic Ca2+-transient amplitudes and contractility during basal stimulation. Importantly, CaMKII inhibition did not compromise systolic fractional Ca2+-release, diastolic SR Ca2+-reuptake via SERCA2a or Ca2+-extrusion via NCX. AS105 is a novel, highly potent ATP-competitive CaMKII inhibitor. In vitro, it effectively reduced SR Ca2+-leak, thus improving SR Ca2+-accumulation and reducing cellular arrhythmogenic correlates, without negatively influencing excitation-contraction coupling. These findings further validate CaMKII as a key target in cardiovascular disease, implicated by genetic, allosteric inhibitors, and pseudo-substrate inhibitors.
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影响因子：
5
作者：
Neef, Stefan;Sag, Can M.;Daut, Maria;Baeumer, Henrik;Grefe, Clemens;El-Armouche, Ali;DeSantiago, Jaime;Pereira, Laetitia;Bers, Donald M.;Backs, Johannes;Maier, Lars S.
通讯作者：
Maier, Lars S.
影响因子：
18.2
作者：
Fischer, Thomas H.;Eiringhaus, Joerg;Sossalla, Samuel
通讯作者：
Sossalla, Samuel
DOI：
10.1016/j.ddmec.2010.07.005
发表时间：
2010-01-01
期刊：
Drug discovery today. Disease mechanisms
影响因子：
--
作者：
Schulman, Howard;Anderson, Mark E
通讯作者：
Anderson, Mark E
影响因子：
9.5
作者：
Kreusser, Michael M.;Lehmann, Lorenz H.;Backs, Johannes
通讯作者：
Backs, Johannes
影响因子：
9.5
作者：
Neef, Stefan;Mann, Christian;Maier, Lars S.
通讯作者：
Maier, Lars S.