CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway.
CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway.
复制标题
CD38 缺乏通过激活 SIRT1/FOXO 介导的抗氧化应激途径保护心脏免受缺血/再灌注损伤。
DOI：
10.1155/2016/7410257
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发表时间：
2016
影响因子：
--
通讯作者：
Xin HB
中科院分区：
文献类型：
--
作者：
Guan XH;Liu XH;Hong X;Zhao N;Xiao YF;Wang LF;Tang L;Jiang K;Qian YS;Deng KY;Ji G;Fu M;Xin HB
缺血/再灌注(I/R)损伤对心肌造成不可逆的氧化应激损伤。我们先前观察到CD38缺乏显著保护小鼠胚胎成纤维细胞(MEF)免受氧化应激诱导的损伤。然而，CD38缺乏是否对心脏I/R损伤具有保护作用还没有被探讨。在这里，我们发现外源性NAD对CD38缺陷小鼠或野生型小鼠的心脏有显著的保护作用，当小鼠缺血30 分钟后再灌流24小时，心肌梗死范围缩小。CD38缺陷对缺氧/复氧(H/R)损伤的保护作用一直被CD38基因敲除的H9c2稳定细胞株所证实。此外，我们还观察到CD38基因的敲除显著抑制了H/R诱导的H9c2细胞内ROS的产生和细胞内钙超载。与正常H9c2细胞相比，缺氧/再灌注损伤后CD38基因敲除细胞中FOXO1和FOX03的表达显著增加。细胞免疫荧光分析显示，CD38基因敲除的H9c2细胞FOXO1核转位显著增加。此外，我们还证明FOXO1核转位的增加与抗氧化剂过氧化氢酶和SOD2的表达增加以及ROS产生酶NOX4的表达减弱有关。综上所述，我们的结果为CD38缺乏通过激活SIRT1/FOXOS介导的抗氧化应激途径保护心脏免受I/R损伤提供了新的证据。
Ischemia/reperfusion (I/R) injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs) from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R) injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca2+ overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.