Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability
Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability
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DOI：
10.1007/s00395-017-0637-y
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发表时间：
2017-07-01
影响因子：
9.5
通讯作者：
Maier, Lars S.
中科院分区：
文献类型：
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作者：
Neef, Stefan;Mann, Christian;Maier, Lars S.
由Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）诱导的肌浆网（SR）Ca 2+渗漏在心房和心室肌纤维化以及心力衰竭重构中起中心作用。因此，治疗SR Ca 2+渗漏已被提出作为一种新的治疗范例，但缺乏用于人类的化合物。SMP-114（“Rimacalib”）是一种新型的口服CaMKII抑制剂，已进入临床II期试验，用于治疗类风湿性关节炎。我们推测SMP-114也可能用于治疗心脏SR Ca 2+泄漏。SMP-114显著降低SR Ca 2+泄漏（通过Ca 2+火花评估）（0.72 +/- 0.33火花/100 mu m/s vs.对照组3.02 +/- 0.91火花/100 mu m/s）和左心室衰竭（0.78 +/- 0.23 vs. 1.69 +/- 0.27 sparks/100 mu m/s）以及鼠心室心肌细胞（0.30 +/- 0.07 vs. 1.50 +/- 0.28 sparks/100 mu m/s）。与较低的SR Ca 2+渗漏相关，我们发现SMP-114抑制自发性致炎性自发Ca 2+释放的发生（每30 s刺激停止0.356 +/- 0.109 vs. 0.927 +/- 0.216事件）。因此，SMP-114改善了30 s暂停期间Ca 2+瞬时振幅（使用Fura-2测量）的静息后增强（52 +/- 5 vs. 37 +/- 4%）。值得注意的是，SMP-114具有这些有益的作用，而不会对整体兴奋-收缩偶联产生负面影响：收缩期Ca 2+释放和单细胞收缩性都没有受到损害，并且在我们的测定中，与所产生的心肌细胞松弛一致的SR Ca 2+再摄取也没有受到SMP-114的损害。SMP-114表现出治疗啮齿动物以及人心房心肌细胞和心力衰竭患者心肌细胞中SR Ca 2+渗漏和因此促心律失常事件的潜力。进一步的研究是必要的，对心脏病的临床应用。
Sarcoplasmic reticulum (SR) Ca2+ leak induced by Ca2+/calmodulin-dependent protein kinase II (CaMKII) is centrally involved in atrial and ventricular arrhythmogenesis as well as heart failure remodeling. Consequently, treating SR Ca2+ leak has been proposed as a novel therapeutic paradigm, but compounds for use in humans are lacking. SMP-114 ("Rimacalib'') is a novel, orally available CaMKII inhibitor developed for human use that has already entered clinical phase II trials to treat rheumatoid arthritis. We speculated that SMP-114 might also be useful to treat cardiac SR Ca2+ leak. SMP-114 significantly reduces SR Ca2+ leak (as assessed by Ca2+ sparks) in human atrial (0.72 +/- 0.33 sparks/100 mu m/s vs. control 3.02 +/- 0.91 sparks/100 mu m/s) and failing left ventricular (0.78 +/- 0.23 vs. 1.69 +/- 0.27 sparks/100 mu m/s) as well as in murine ventricular cardiomyocytes (0.30 +/- 0.07 vs. 1.50 +/- 0.28 sparks/100 mu m/s). Associated with lower SR Ca2+ leak, we found that SMP-114 suppressed the occurrence of spontaneous arrhythmogenic spontaneous Ca2+ release (0.356 +/- 0.109 vs. 0.927 +/- 0.216 events per 30 s stimulation cessation). In consequence, post-rest potentiation of Ca2+-transient amplitude (measured using Fura-2) during the 30 s pause was improved by SMP-114 (52 +/- 5 vs. 37 +/- 4%). Noteworthy, SMP-114 has these beneficial effects without negatively impairing global excitation-contraction coupling: neither systolic Ca2+ release nor single cell contractility was compromised, and also SR Ca2+ reuptake, in line with resulting cardiomyocyte relaxation, was not impaired by SMP-114 in our assays. SMP-114 demonstrated potential to treat SR Ca2+ leak and consequently proarrhythmogenic events in rodent as well as in human atrial cardiomyocytes and cardiomyocytes from patients with heart failure. Further research is necessary towards clinical use in cardiac disease.