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Revascularization and limb salvage following critical limb ischemia by nanoceria-induced Ref-1/APE1-dependent angiogenesis
Biomaterials ( IF 14.0 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.biomaterials.2020.119919
In-Su Park , Chinmaya Mahapatra , Ji Sun Park , Khandmaa Dashnyam , Jong-Wan Kim , Jin Chul Ahn , Phil-Sang Chung , Dong Suk Yoon , Nandin Mandakhbayar , Rajendra K. Singh , Jung-Hwan Lee , Kam W. Leong , Hae-Won Kim

In critical limb ischemia (CLI), overproduction of reactive oxygen species (ROS) and impairment of neovascularization contribute to muscle damage and limb loss. Cerium oxide nanoparticles (CNP, or ‘nanoceria’) possess oxygen-modulating properties which have shown therapeutic utility in various disease models. Here we show that CNP exhibit pro-angiogenic activity in a mouse hindlimb ischemia model, and investigate the molecular mechanism underlying the pro-angiogenic effect. CNP were injected into a ligated region of a femoral artery, and tissue reperfusion and hindlimb salvage were monitored for 3 weeks. Tissue analysis revealed stimulation of pro-angiogenic markers, maturation of blood vessels, and remodeling of muscle tissue following CNP administration. At a dose of 0.6 mg CNP, mice showed reperfusion of blood vessels in the hindlimb and a high rate of limb salvage (71%, n = 7), while all untreated mice (n = 7) suffered foot necrosis or limb loss. In vitro, CNP promoted endothelial cell tubule formation via the Ref-1/APE1 signaling pathway, and the involvement of this pathway in the CNP response was confirmed in vivo using immunocompetent and immunodeficient mice and by siRNA knockdown of APE1. These results demonstrate that CNP provide an effective treatment of CLI with excessive ROS by scavenging ROS to improve endothelial survival and by inducing Ref-1/APE1-dependent angiogenesis to revascularize an ischemic limb.



中文翻译:

纳米二氧化铈诱导的Ref-1 / APE1依赖性血管新生导致严重肢体缺血后的血运重建和肢体抢救

在严重肢体缺血(CLI)中,活性氧(ROS)的过度产生和新血管形成的损害会导致肌肉损伤和肢体丢失。氧化铈纳米粒子(CNP或“纳米藻”)具有氧调节特性,已在各种疾病模型中显示出治疗用途。在这里,我们显示CNP在小鼠后肢缺血模型中显示促血管生成活性,并研究促血管生成作用的分子机制。将CNP注射入股动脉的结扎区域,并监测组织再灌注和后肢抢救3周。组织分析显示,CNP给药后,促血管生成标记物受到刺激,血管成熟,肌肉组织重塑。在0.6 mg CNP的剂量下,在体外,CNP通过Ref-1 / APE1信号通路促进内皮细胞小管形成,并在体内使用免疫活性和免疫缺陷小鼠以及通过APE1的siRNA敲除证实了该通路参与CNP反应这些结果表明,CNP可通过清除ROS来改善内皮细胞的存活,并诱导Ref-1 / APE1依赖性血管生成来使缺血性肢体重新血管化,从而为ROS过多的CLI提供有效的治疗方法。

更新日期:2020-02-28
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