Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes.
Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes.
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DOI：
10.1016/j.yjmcc.2010.01.020
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发表时间：
2010-06
影响因子：
5
通讯作者：
Most P
中科院分区：
文献类型：
--
作者：
Voelkers M;Salz M;Herzog N;Frank D;Dolatabadi N;Frey N;Gude N;Friedrich O;Koch WJ;Katus HA;Sussman MA;Most P
心脏肥大是心力衰竭（HF）和猝死的独立风险。破译依赖于细胞外钙（Ca 2+）内流的信号通路，控制正常和病理性心脏生长，可能使新的治疗靶点的识别。本研究的目的是确定Ca 2+释放激活的Ca 2+（CRAC）通道Orai 1和基质相互作用分子1（Stim 1）在出生后心肌细胞钙库操作的Ca 2+内流（SOCE）中的作用以及对正常和肥大的出生后心肌细胞生长的影响。采用siRNA介导的基因沉默，培养的新生大鼠心室心肌细胞与间接免疫荧光，荧光Ca 2+成像和位点特异性蛋白磷酸化和实时mRNA表达分析的组合，我们首次表明，Orai 1和Stim 1都存在于心肌细胞中，并需要SOCE由于胞内Ca 2+存储耗尽毒胡萝卜素。Stim 1-KD而不是Orai 1-KD显着降低了舒张期Ca 2+水平和肌浆网（SR）中咖啡因释放的Ca 2+。相反，Orai 1-KD而不是Stim 1-KD显著降低了基础NRCM细胞大小、anp和bnp mRNA水平以及钙调神经磷酸酶（CnA）信号通路的活性，尽管Orai 1和Stim 1蛋白在基础条件下同样降低了钙调蛋白激酶II（CamKII）和ERK 1/2活性。Orai 1-和Stim 1-KD都能完全阻断苯肾上腺素（PE）介导的NRCM肥大生长，并通过抑制Gq蛋白介导的CaMKII和ERK 1/2信号通路的激活来增强利钠因子的表达。有趣的是，只有Orai 1-KD而不是Stim 1-KD阻止了Gq介导的CaN依赖性促肥大信号传导。这项研究首次表明，Orai 1和Stim 1在心肌细胞SOCE中起关键作用，在体外调节正常和肥大的出生后心脏生长。
Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca2+) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca2+ release-activated Ca2+ (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomycoyte store-operated Ca2+ entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth. Employing a combination of siRNA-mediated gene silencing, cultured neonatal rat ventricular cardiomyocytes together with indirect immunofluorescence, epifluorescent Ca2+ imaging and site-specific protein phosphorylation and real-time mRNA expression analysis, we show for the first time that both Orai1 and Stim1 are present in cardiomyocytes and required for SOCE due to intracellular Ca2+ store depletion by thapsigargin. Stim1-KD but not Orai1-KD significantly decreased diastolic Ca2+ levels and caffeine-releasable Ca2+ from the sarcoplasmic reticulum (SR). Conversely, Orai1-KD but not Stim1-KD significantly diminished basal NRCM cell size, anp and bnp mRNA levels and activity of the calcineurin (CnA) signaling pathway although diminishing both Orai1 and Stim1 protein similarly attenuated calmodulin kinase II (CamKII) and ERK1/2 activity under basal conditions. Both Orai1- and Stim1-KD completely abrogated phenylephrine (PE) mediated hypertrophic NRCM growth and enhanced natriuretic factor expression by inhibiting Gq-protein conveyed activation of the CaMKII and ERK1/2 signaling pathway. Interestingly, only Orai1-KD but not Stim1-KD prevented Gq-mediated CaN-dependent prohypertrophic signalling. This study shows for the first time that both Orai1 and Stim1 have a key role in cardiomyocyte SOCE regulating both normal and hypertrophic postnatal cardiac growth in vitro.
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影响因子：
4.8
作者：
Most, P;Boerries, M;Remppis, A
通讯作者：
Remppis, A
影响因子：
64.8
作者：
Prakriya, Murali;Feske, Stefan;Hogan, Patrick G.
通讯作者：
Hogan, Patrick G.
影响因子：
21.3
作者：
Stiber, Jonathan;Hawkins, April;Rosenberg, Paul
通讯作者：
Rosenberg, Paul
影响因子：
15.9
作者：
Wu, X;Zhang, T;Bers, DM
通讯作者：
Bers, DM
DOI：
10.1152/ajpheart.00162.2003
发表时间：
2004-03-01
影响因子：
4.8
作者：
Hunton, DL;Zou, LY;Marchase, RB
通讯作者：
Marchase, RB