Prion Protein Expression and Functional Importance in Developmental Angiogenesis: Role in Oxidative Stress and Copper Homeostasis
Prion Protein Expression and Functional Importance in Developmental Angiogenesis: Role in Oxidative Stress and Copper Homeostasis
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DOI：
10.1089/ars.2012.4637
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发表时间：
2013-02-01
影响因子：
6.6
通讯作者：
Benharouga, Mohamed
中科院分区：
文献类型：
--
作者：
Alfaidy, Nadia;Chauvet, Sylvain;Benharouga, Mohamed
目的：已经令人信服地表明，氧化应激和金属（例如铜（Cu））失调引起的毒性与先兆子痫和宫内生长迟缓（IUGR）的发展密切相关，这是人类妊娠最具威胁的病症。然而，用于控制这些影响的机制还远未被理解。细胞朊病毒蛋白 (PrPC) 是结合铜并确保细胞免受氧化应激的保护的蛋白质之一，它是一种糖基磷脂酰肌醇锚定的糖蛋白，据我们报道，它在人胎盘中高度表达。在此，我们使用人胎盘和滋养层细胞在体外研究了 PrPC 在 Cu 和氧化应激稳态中的病理生理学作用，并使用三种小鼠品系（C57Bl6、PrPC 敲除小鼠 [PrP-/-] 和 PrPC 过表达小鼠 [Tga20]）在体内研究了 PrPC 在 Cu 和氧化应激稳态中的病理生理学作用。结果：在细胞水平上，PrPC 在多种血管生成过程（增殖、迁移和管状组织）中建立了针对氧化应激的保护作用。在动物模型中，妊娠小鼠缺乏（PrP-/-）或过度表达（Tga20）PrPC会导致严重的IUGR，这与窝产仔数减少、铜稳态变化、氧化应激反应增加、缺氧环境发展、胎盘功能衰竭以及后代生长缺陷的维持相关，甚至在产后7.5个月时也是如此。创新：PrPC 可以作为特发性 IUGR 疾病的标志物。结论：这些发现证明了 PrPC 在发育过程中的应激保护作用，并提出 PrPC 失调是 IUGR 的一个新的致病因素。抗氧化剂。氧化还原信号。 18、400-411。
Aim: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrPC), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrPC in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrPC knockout mice [PrP-/-], and PrPC overexpressing mice [Tga20]). Results: At the cellular level, PrPC protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP-/-) or overexpression (Tga20) of PrPC in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. Innovation: PrPC could serve as a marker for the idiopathic IUGR disease. Conclusion: These findings demonstrate the stress-protective role of PrPC during development, and propose PrPC dysregulation as a novel causative element of IUGR. Antioxid. Redox Signal. 18, 400-411.