CaMKII mediates cadmium induced apoptosis in rat primary osteoblasts through MAPK activation and endoplasmic reticulum stress
CaMKII mediates cadmium induced apoptosis in rat primary osteoblasts through MAPK activation and endoplasmic reticulum stress
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CaMKII 通过 MAPK 激活和内质网应激介导镉诱导的大鼠原代成骨细胞凋亡
DOI：
10.1016/j.tox.2018.06.002
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发表时间：
2018-08-01
期刊：
影响因子：
4.5
通讯作者：
Liu, Zongping
中科院分区：
文献类型：
--
作者：
Liu, Wei;Xu, Chao;Liu, Zongping
Ca ~（2+）是细胞内多种代谢途径中的重要离子。内质网（ER）是细胞内主要的钙库，ER钙稳态在细胞凋亡的调控中起着关键作用。我们以前已经表明，镉（Cd）诱导成骨细胞（OBs）的凋亡，伴随着细胞质钙离子的增加。由于钙离子在镉诱导的OBs凋亡中的作用还不清楚，我们研究了镉暴露对大鼠OBs细胞内Ca 2 + CaMKII磷酸化的影响，以及诱导凋亡的途径。结果表明，镉（Cd）通过释放内质网中的Ca 2+和细胞外基质中的Ca 2+内流，引起OB细胞内Ca 2+（[Ca 2 +]（i））升高。Cd诱导[Ca ~（2+）]（i）CaMK Ⅱ的升高和磷酸化，CaMK Ⅱ可能参与了MAPK的活化，并通过改变Bax/Bcl-2的表达比例参与了Cd诱导的线粒体凋亡。同时，CaMKII磷酸化激活未折叠蛋白反应（UPR）在镉处理过程中，可以通过激活caspase-12，使ER凋亡途径。提示CaMK Ⅱ在镉诱导的内质网凋亡和MAPK激活中起重要作用。我们的数据提供了新的见解的机制，在OBs的细胞凋亡后，镉暴露。这为今后研究CaMKII抑制剂在镉暴露所致骨质疏松症中的临床治疗应用提供了理论基础。
Ca2+ is an important ion in various intracellular metabolic pathways. Endoplasmic reticulum (ER) is a major intracellular calcium store and ER calcium homeostasis plays a key part in the regulation of apoptosis. We have previously shown that Cadmium (Cd) induces apoptosis in osteoblasts (OBs), accompany by increased cytoplasmic calcium. As the role of calcium in OBs apoptosis induced by Cd has not been clarified we investigated the effects of Cd exposure in rat OBs on intracellular Ca2+ CaMKII phosphorylation, and the pathways implicated in inducing apoptosis. The results showed that cadmium(Cd) induced elevation of intracellular Ca2+ ([Ca2+](i)) in OBs by the release of Ca2+ from ER and the inflow of Ca2+ from the extracellular matrix. Cd induced [Ca2+](i) elevation and phosphorylation of CaMKII which might be involved in activation of MAPKs and participated in Cd-induced mitochondrial apoptosis through the alteration of the ratio of Bax/Bcl-2 expression. Meanwhile, CaMKII phosphorylation activated unfolded protein response (UPR) during cadmium treatment and could enable the ER apoptosis pathway through the activation of caspase-12. These results indicated that CaMKII plays an important role in Cd induced ER apoptosis and MAPK activation. Our data provide new insights into the mechanisms underlying apoptosis in OBs following Cd exposure. This provides a theoretical basis for future investigations into the clinical therapeutic application of CaMKII inhibitors in osteoporosis induced by Cd exposure.