CaMKIIδ meditates phenylephrine induced cardiomyocyte hypertrophy through store-operated Ca2+ entry
CaMKIIδ meditates phenylephrine induced cardiomyocyte hypertrophy through store-operated Ca2+ entry
复制标题
CaMKII δ 通过钙库操纵的 Ca2 进入介导去氧肾上腺素诱导的心肌细胞肥大
DOI：
10.1016/j.carpath.2016.11.004
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发表时间：
2017-03-01
影响因子：
3.7
通讯作者：
Gui, Le
中科院分区：
文献类型：
--
作者：
Ji, Yawei;Guo, Xin;Gui, Le
有证据表明，钙库操纵的钙内流（SOCE）参与心肌细胞肥大。SOCE导致苯肾上腺素（PE）刺激后心肌肥大的信号转导机制尚未完全了解。Ca 2 +/钙调素依赖性蛋白激酶II δ（CaMKII δ）在调节心肌细胞内Ca 2+止血和功能中起重要作用。本研究旨在探讨CaMK Ⅱ δ在PE诱导的心肌肥厚中的作用及其分子信号机制。我们使用从Sprague道利大鼠左心室分离的新生心肌细胞的原代培养物来研究CaMK II δ对心肌肥大和细胞内Ca 2+动员的影响。我们发现，在PE诱导的肥大心肌细胞中，CaMK Ⅱ δ的表达增强。CaMKII δ siRNA、CaMKII抑制剂KN 93和SOCE阻断剂BTP 2减弱了CaMKII δ表达的增加，并使肥大标志物、心钠素和脑钠素以及PE刺激诱导的心肌细胞大小正常化。基质相互作用分子1和Orai 1（SOCE的基本成分）的蛋白水平在肥大心肌细胞中也得到增强，这些细胞通过CaMKII delta siRNA和KN 93治疗正常化。肥大心肌细胞显示钙池耗竭后Ca 2+瞬时峰值增加，这被SOCE阻断剂BTP 2、CaMKII delta siRNA和KN 93抑制。在PE处理的心肌细胞中，通过Ca 2+释放激活的Ca 2+通道的Ca 2+电流增加，并被CaMK II delta siRNA和KN 93减弱。这些数据表明，PE诱导的心肌肥大需要一个复杂的信号通路，涉及激活CaMKII δ和SOCE。总之，这些研究表明，CaMK Ⅱ δ的上调可能通过激活心肌细胞中表达的SOCE参与PE诱导的心肌肥大。(C)2016 Elsevier Inc. All rights reserved.
Evidence suggests that store-operated Ca2+ entry (SOCE) is involved in the hypertrophy of cardiomyocytes. The signaling mechanisms of SOCE contributing to cardiac hypertrophy following phenylephrine (PE) stimulation are not fully understood. Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) plays an important role in regulating intracellular Ca2+ hemostasis and function in the cardimyocytes. This study is aimed to determine the role of CaMKII delta in regulating the PE-inducedmyocardial hypertrophy and the associated molecular signaling mechanisms. We used primary cultures of neonatal cardimyocytes isolated from the left ventricle of Sprague Dawley rats to investigate the effects of CaMKII delta on myocardial hypertrophy and intracellular Ca2+ mobilization. We found that the expression of CaMKII delta was enhanced in PE-induced hypertrophic cardiomyocytes. CaMKII delta siRNA, CaMKII inhibitor KN93, and SOCE blocker BTP2 attenuated the increase in the expression of CaMKII delta and normalized the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide, and size of cardiomyocytes induced by PE stimulation. The protein level of stromal interaction molecule 1 and Orai1, the essential components of the SOCE, is also enhanced in hypertrophic cardiomyocytes, which were normalized by CaMKII delta siRNA and KN93 treatment. Hypertrophic cardiomyocytes showed an increase in the peak of Ca2+ transient following store depletion, which was inhibited by SOCE blocker BTP2, CaMKII delta siRNA, and KN93. The Ca2+ currents through Ca2+ release-activated Ca2+ channels were increased in PE-treated cardiomyocytes and were attenuated by CaMKII delta siRNA and KN93. These data indicate that PE-induced myocardial hypertrophy requires a complex signaling pathway that involves activation of both CaMKII delta and SOCE. In conclusion, these studies reveal that up-regulation of CaMKII delta may contribute to the PE-induced myocardial hypertrophy through the activation of SOCE expressed in the cardiomyocytes. (C) 2016 Elsevier Inc. All rights reserved.