Mouse embryonic fibroblasts from CD38 knockout mice are resistant to oxidative stresses through inhibition of reactive oxygen species production and Ca2+ overload
Mouse embryonic fibroblasts from CD38 knockout mice are resistant to oxidative stresses through inhibition of reactive oxygen species production and Ca2+ overload
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DOI：
10.1016/j.bbrc.2010.07.040
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发表时间：
2010-08-20
影响因子：
3.1
通讯作者：
Xin, Hong-Bo
中科院分区：
文献类型：
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作者：
Ge, Yan;Jiang, Wei;Xin, Hong-Bo
CD38是一种多功能酶，同时具有ADP-核糖基环化酶和cADPR水解酶活性，能够将NAD(+)裂解为环状ADP核糖(cADPR)并将cADPR水解为ADPR。据报道，CD38敲除(CD38(-/-))小鼠的许多组织中cADPR显着降低，NAD显着升高。环状 ADPR 是细胞内 Ca2+ 动员的有效第二信使，NAD 是细胞能量的关键细胞代谢物，也是细胞内多种信号通路的关键调节剂。我们假设 CD38 敲除可能通过提高 NAD 和降低 cADPR 对氧化应激产生保护作用。在本研究中，我们观察到与野生型MEF（WT MEF）相比，CD38（-/-）小鼠的小鼠胚胎成纤维细胞（MEF）对H2O2损伤和缺氧/复氧等氧化应激具有显着的抵抗力。我们进一步发现，在缺氧/复氧过程中，与WT MEF相比，CD38(-/-) MEF中活性氧(ROS)的产生和细胞内Ca2+([Ca-2](i))的浓度显着降低。与这些结果一致的是，在 CD38(-/-) MEF 中观察到 Nox1（负责 ROS 生成的酶之一）的 mRNA 水平显着降低。此外，我们发现钙离子载体离子霉素可以以剂量依赖性方式提高WT MEF中Nox1 mRNA的转录，表明Nox1 mRNA的表达可以通过细胞内[Ca2+]的升高来调节。因此我们得出结论，CD38(-/-) MEFs通过抑制细胞内Ca2+超载和ROS产生来抵抗氧化应激，这可能是通过Ca2+介导的Nox1表达抑制来调节的。我们的数据应该为阐明 CD38 在氧化应激中的作用提供见解，并为处理缺血/再灌注相关疾病提供新的视角。 (c) 2010 Elsevier Inc. 保留所有权利。
CD38 is a multifunctional enzyme that has both ADP-ribosyl cyclase and cADPR hydrolase activities, being capable of cleaving NAD(+) to cyclic ADP ribose (cADPR) and hydrolyzing cADPR to ADPR. It has been reported that there is markedly a reduction of cADPR and elevation of NAD in many tissues from CD38 knockout (CD38(-/-)) mice. Cyclic ADPR is a potent second messenger for intracellular Ca2+ mobilization, and NAD is a key cellular metabolite for cellular energetic and a crucial regulator for multiple signaling pathways in cells. We hypothesize that CD38 knockout may have a protective effect in oxidative stresses through elevating NAD and decreasing cADPR. In the present study, we observed that the mouse embryonic fibroblasts (MEFs) from CD38(-/-) mice were significantly resistant to oxidative stress such as H2O2 injury and hypoxia/reoxygenation compared with wild type MEFs (WT MEFs). We further found that production of reactive oxygen species (ROS) and concentrations of intracellular Ca2+ ([Ca-2](i)) in CD38(-/-) MEFs were markedly reduced compared with WT MEFs during hypoxia/reoxygenation. Coincidence with these results, a remarkably lower mRNA level of Nox1, one of the enzymes responsible for ROS generation, was observed in CD38(-/-) MEFs. Furthermore, we found that transcription of Nox1 mRNA in WT MEFs could be elevated by calcium ionophore ionomycin in a dose-dependent manner, indicating that the expression of Nox1 mRNA can be regulated by elevation of intracellular [Ca2+]. Therefore we concluded that CD38(-/-) MEFs are resistant to oxidative stresses through inhibiting intracellular Ca2+ overload and ROS production which may be regulated by Ca2+-mediated inhibition of Nox1 expression. Our data should provide an insight for elucidating the roles of CD38 in oxidative stresses and a novel perspective of dealing with the ischemia/reperfusion-related diseases. (c) 2010 Elsevier Inc. All rights reserved.