Adrenergic DNA damage of embryonic pluripotent cells via β2 receptor signalling.
Adrenergic DNA damage of embryonic pluripotent cells via β2 receptor signalling.
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通过 β2 受体信号传导对胚胎多能细胞的肾上腺素 DNA 损伤
DOI：
10.1038/srep15950
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发表时间：
2015-10-30
影响因子：
4.6
通讯作者：
Zhu L
中科院分区：
文献类型：
--
作者：
Sun F;Ding XP;An SM;Tang YB;Yang XJ;Teng L;Zhang C;Shen Y;Chen HZ;Zhu L
胚胎多能细胞对遗传毒性敏感，尽管它们需要更严格的基因组完整性以避免损害多个细胞谱系和后代。然而，肾上腺素能应激是否能引起体细胞基因组损伤尚不清楚。我们发现肾上腺素能应激介质通过β2肾上腺素能受体/腺苷酸环化酶/cAMP/PKA信号通路诱导细胞内活性氧（ROS）积累而引起细胞DNA损伤。肾上腺素能应激激动剂肾上腺素、去甲肾上腺素和异丙肾上腺素可引起胚胎干细胞和胚胎癌干细胞的DNA损伤和凋亡。β2受体偶联信号分子模拟了这种效应，并通过选择性阻断β2受体和抑制受体信号通路消除了这种效应。针对ES细胞β2受体的RNA干扰使ES细胞具有抵抗DNA损伤和凋亡的能力。此外，肾上腺素能刺激引起细胞中ROS的持续积累，β2受体阻断剂可消除这种作用; ROS的淬灭可逆转诱导的DNA损伤。这一发现将提高对肾上腺素能受体亚型信号传导机制中干细胞调节生理学/病理生理学的理解。
Embryonic pluripotent cells are sensitive to genotoxicity though they need more stringent genome integrity to avoid compromising multiple cell lineages and subsequent generations. However it remains unknown whether the cells are susceptible to adrenergic stress which can induce somatic cell genome lesion. We have revealed that adrenergic stress mediators cause DNA damage of the cells through the β2 adrenergic receptor/adenylate cyclase/cAMP/PKA signalling pathway involving an induction of intracellular reactive oxygen species (ROS) accumulation. The adrenergic stress agonists adrenaline, noradrenaline, and isoprenaline caused DNA damage and apoptosis of embryonic stem (ES) cells and embryonal carcinoma stem cells. The effects were mimicked by β2 receptor-coupled signalling molecules and abrogated by selective blockade of β2 receptors and inhibition of the receptor signalling pathway. RNA interference targeting β2 receptors of ES cells conferred the cells the ability to resist the DNA damage and apoptosis. In addition, adrenergic stimulation caused a consistent accumulation of ROS in the cells and the effect was abrogated by β2 receptor blockade; quenching of ROS reversed the induced DNA damage. This finding will improve the understanding of the stem cell regulatory physiology/pathophysiology in an adrenergic receptor subtype signalling mechanism.