Dihydroceramide-based Response to Hypoxia
Dihydroceramide-based Response to Hypoxia
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DOI：
10.1074/jbc.m111.297994
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发表时间：
2011-11-04
影响因子：
4.8
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
--
作者：
Devlin, Cecilia M.;Lahm, Tim;Petrache, Irina
为了了解神经酰胺对缺氧的反应机制，我们对各种缺氧条件（0.2-5%氧气）引起的神经酰胺种类进行了基于质谱的调查。我们描述了一个快速的，时间依赖性的，显着的上调二氢神经酰胺（DHCs）在哺乳动物细胞和缺氧大鼠的肺。增加影响所有DHC物种，并与缺氧的深度和持续时间成正比，范围从2-（1小时）至10倍（24小时），1小时后完全恢复正常的复氧增加神经酰胺的费用。我们证明了一个基于DHC的缺氧反应发生在一个缺氧诱导因子独立的方式，是由DHC去饱和酶（DEGS）在从头神经酰胺途径催化。低氧对DHC分子种类的影响及其对细胞增殖的抑制作用均通过在常氧条件下通过siRNA敲低DEGS 1或DEGS 2来再现。相反，DEGS 1或DEGS 2的过表达减弱了DHC的积累，并增加了缺氧期间的细胞增殖。基于DHC积累的幅度和动力学，DHCs的酶促去饱和满足了生理缺氧条件下氧传感器的标准，调节了神经酰胺代谢的生物活性成分之间的平衡。
To understand the mechanisms of ceramide-based responses to hypoxia, we performed a mass spectrometry-based survey of ceramide species elicited by a wide range of hypoxic conditions (0.2-5% oxygen). We describe a rapid, time-dependent, marked up-regulation of dihydroceramides (DHCs) in mammalian cells and in the lungs of hypoxic rats. The increase affected all DHC species and was proportional with the depth and duration of hypoxia, ranging from 2-(1 h) to 10-fold (24 h), with complete return to normal after 1 h of reoxygenation at the expense of increased ceramides. We demonstrate that a DHC-based response to hypoxia occurs in a hypoxia-inducible factor-independent fashion and is catalyzed by theDHCdesaturase (DEGS) in the de novo ceramide pathway. Both the impact of hypoxia on DHC molecular species and its inhibitory effect on cell proliferation were reproduced by knockdown of DEGS1 or DEGS2 by siRNA during normoxia. Conversely, overexpression of DEGS1 or DEGS2 attenuated the DHC accumulation and increased cell proliferation during hypoxia. Based on the amplitude and kinetics of DHC accumulation, the enzymatic desaturation of DHCs fulfills the criteria of an oxygen sensor across physiological hypoxic conditions, regulating the balance between biologically active components of ceramide metabolism.