Overexpression of Nrdp1 in the heart exacerbates doxorubicin-induced cardiac dysfunction in mice.
Overexpression of Nrdp1 in the heart exacerbates doxorubicin-induced cardiac dysfunction in mice.
复制标题
心脏中 Nrdp1 的过度表达会加剧阿霉素诱导的小鼠心脏功能障碍
DOI：
10.1371/journal.pone.0021104
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Li HH
中科院分区：
文献类型：
--
作者：
Zhang Y;Kang YM;Tian C;Zeng Y;Jia LX;Ma X;Du J;Li HH
背景心肌细胞死亡和氧化应激的产生与阿霉素(DOX)诱导的心功能障碍有关。E3连接酶Nrdp1在调节细胞凋亡、炎症和产生活性氧(ROS)方面发挥重要作用，而ROS可能导致心力衰竭。然而，Nrdp1在DOX诱导的心脏损伤中的作用仍有待确定。方法与结果我们观察了DOX对新生大鼠心肌细胞和小鼠心肌组织中Nrdp1过表达的影响。用含GFP的腺病毒(Ad-GFP)、野生型Nrdp1(Ad-Nrdp1)和显性-阴性Nrdp1(Ad-Dn-Nrdp1)感染心肌细胞，然后用DOX处理24小时。DOX处理增加了细胞死亡和凋亡，Ad-Nrdp1感染增强了这些作用，而Ad-Dn-Nrdp1感染减弱了这些作用。此外，与野生型小鼠(WT)相比，单次注射DOX(20 mg/kg)5天后，Nrdp1转基因小鼠(TG)心功能下降，细胞凋亡、自噬和氧化应激增加(P<；0.01)。注射DOX 10天后，Nrdp1Tg组小鼠的存活率明显低于WT组(P<；0.01)。结论/意义这些结果与Akt、细胞外信号调节激酶1/2(ERK1/2)和信号转导与转录激活因子3(STAT3)信号通路的激活减少有关。Nrdp1可能是DOX治疗后心功能不全发生的关键介质，并与Akt、ERK1/2和STAT3的抑制有关。Nrdp1可能成为预防DOX心脏毒性作用的新靶点。
Background Cardiac cell death and generation of oxidative stress contribute to doxorubicin (DOX)-induced cardiac dysfunction. E3 ligase Nrdp1 plays a critical role in the regulation of cell apoptosis, inflammation and production of reactive oxygen species (ROS), which may contribute to heart failure. However, the role of Nrdp1 in DOX-induced cardiac injury remains to be determined. Methods and Results We examined the effect of Nrdp1 overexpression with DOX treatment in rat neonatal cardiomyocytes and mouse heart tissue. Cardiomyocytes were infected with adenovirus containing GFP (Ad-GFP), Nrdp1 wild-type (Ad-Nrdp1) or the dominant-negative form of Nrdp1 (Ad-Dn-Nrdp1), then treated with DOX for 24 hr. DOX treatment increased cell death and apoptosis, with Ad-Nrdp1 infection enhancing these actions but Ad-Dn-Nrdp1 infection attenuating these effects. Furthermore, 5 days after a single injection of DOX (20 mg/kg, intraperitoneally), Nrdp1 transgenic mice (TG) showed decreased cardiac function and increased apoptosis, autophagy and oxidative stress as compared with wild-type (WT) mice (P<0.01). Survival rate was significantly lower in Nrdp1 TG mice than in WT mice 10 days after DOX injection (P<0.01). Conclusions/Significance These results were associated with decreased activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Nrdp1 may be a key mediator in the development of cardiac dysfunction after DOX treatment and associated with inhibition of Akt, ERK1/2 and STAT3. Nrdp1 may be a new therapeutic target in protecting against the cardiotoxic effects of DOX.
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