Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy
Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy
复制标题
异丙酚通过 ATG5 和钙依赖性自噬调节影响体外小鼠胚胎成纤维细胞的存活和增殖
DOI：
10.1038/s41401-019-0303-z
复制
发表时间：
2019-10
影响因子：
8.2
通讯作者：
Hua-feng Wei
中科院分区：
文献类型：
--
作者：
Zhen-dong Xu;Yong Wang;Ge Liang;Zhi-qiang Liu;Wu-hua Ma;Charleen T Chu;Hua-feng Wei
丙泊酚是一种常用的静脉麻醉剂，已发现其影响细胞存活和增殖，尤其是在生命早期。我们前期的研究表明，异丙酚诱导的神经退行性变和神经发生与细胞自噬密切相关。本研究探讨了自噬相关基因5（ATG 5）在丙泊酚诱导的小鼠胚胎成纤维细胞（MEF）自噬中的作用。我们发现，ATG 5在功能上与丙泊酚诱导的细胞存活和损伤相关：丙泊酚在临床相关剂量（10 µM）下显著增强细胞存活和增殖，但在ATG 5-/-MEF中在极高浓度（200 µM）下引起细胞死亡，但在WT细胞中则不然。ATG 5-/-MEF的双重作用可被胞内Ca ~（2+）通道拮抗剂阻断。我们还发现，仅在ATG 5-/-MEF中，异丙酚在10 µM和200 µM浓度下分别引起中度（促进细胞生长）和极高（导致细胞凋亡）的胞浆Ca 2+升高。此外，与WT细胞相比，ATG 5-/-MEF本身在胞质空间和内质网中释放更多的Ca 2+，这表明自噬缺陷使细胞内钙信号更容易受到外部刺激（丙泊酚）的影响。总之，我们的研究结果表明，ATG 5通过影响细胞内Ca 2+稳态在丙泊酚调节细胞存活和增殖中起着至关重要的作用。
Propofol is a commonly used intravenous anesthetic agent, which has been found to affect cell survival and proliferation especially in early life. Our previous studies show that propofol-induced neurodegeneration and neurogenesis are closely associated with cell autophagy. In the present study we explored the roles of autophagy-related gene 5 (ATG5) in propofol-induced autophagy in mouse embryonic fibroblasts (MEF) in vitro. We showed that ATG5 was functionally related to propofol-induced cell survival and damage: propofol significantly enhanced cell survival and proliferation at a clinically relevant dose (10 µM), but caused cell death at an extremely high concentration (200 µM) in ATG5-/-MEF, but not in WT cells. The dual effects found in ATG5-/-MEF could be blocked by intracellular Ca2+channel antagonists. We also found that propofol evoked a moderate (promote cell growth) and extremely high (cause apoptosis) cytosolic Ca2+elevation at the concentrations of 10 µM and 200 µM, respectively, only in ATG5-/-MEF. In addition, ATG5-/-MEF themselves released more Ca2+in cytosolic space and endoplasmic reticulum compared with WT cells, suggesting that autophagy deficiency made intracellular calcium signaling more vulnerable to external stimuli (propofol). Altogether, our results reveal that ATG5 plays a crucial role in propofol regulation of cell survival and proliferation by affecting intracellular Ca2+homeostasis.
登录
查看更多内容
DOI：
10.1084/jem.20061303
发表时间：
2007-01-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pua HH;Dzhagalov I;Chuck M;Mizushima N;He YW
通讯作者：
He YW
影响因子：
8.8
作者：
O'Sullivan TE;Geary CD;Weizman OE;Geiger TL;Rapp M;Dorn GW 2nd;Overholtzer M;Sun JC
通讯作者：
Sun JC
影响因子：
8.8
作者：
Yang H;Liang G;Hawkins BJ;Madesh M;Pierwola A;Wei H
通讯作者：
Wei H
影响因子：
7
作者：
Watson AS;Riffelmacher T;Stranks A;Williams O;De Boer J;Cain K;MacFarlane M;McGouran J;Kessler B;Khandwala S;Chowdhury O;Puleston D;Phadwal K;Mortensen M;Ferguson D;Soilleux E;Woll P;Jacobsen SE;Simon AK
通讯作者：
Simon AK
影响因子：
21.3
作者：
Medina DL;Di Paola S;Peluso I;Armani A;De Stefani D;Venditti R;Montefusco S;Scotto-Rosato A;Prezioso C;Forrester A;Settembre C;Wang W;Gao Q;Xu H;Sandri M;Rizzuto R;De Matteis MA;Ballabio A
通讯作者：
Ballabio A