Park In-Su, Mahapatra Chinmaya, Park Ji Sun, Dashnyam Khandmaa, Kim Jong-Wan, Ahn Jin Chul, Chung Phil-Sang, Yoon Dong Suk, Mandakhbayar Nandin, Singh Rajendra K, Lee Jung-Hwan, Leong Kam W, Kim Hae-Won
Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, South Korea; Beckman Laser Institute Korea, Dankook University, Cheonan, 31116, South Korea; Cell Therapy Center, Ajou University Medical Center, Suwon, South Korea.
Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, South Korea; Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, South Korea.
Biomaterials. 2020 Jun;242:119919. doi: 10.1016/j.biomaterials.2020.119919. Epub 2020 Feb 27.
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.
在严重肢体缺血（CLI）中，活性氧（ROS）的过度产生和新血管形成受损会导致肌肉损伤和肢体丧失。氧化铈纳米颗粒（CNP，或“纳米氧化铈”）具有氧调节特性，已在各种疾病模型中显示出治疗效用。在此，我们表明CNP在小鼠后肢缺血模型中具有促血管生成活性，并研究了促血管生成作用的分子机制。将CNP注入股动脉结扎区域，并监测组织再灌注和后肢挽救情况3周。组织分析显示，给予CNP后，促血管生成标志物受到刺激，血管成熟，肌肉组织发生重塑。在0.6毫克CNP的剂量下，小鼠后肢血管出现再灌注，肢体挽救率很高（71%，n = 7），而所有未治疗的小鼠（n = 7）均出现足部坏死或肢体丧失。在体外，CNP通过Ref-1/APE1信号通路促进内皮细胞小管形成，并且使用免疫活性和免疫缺陷小鼠以及通过对APE1进行小干扰RNA敲低在体内证实了该通路参与CNP反应。这些结果表明，CNP通过清除ROS以改善内皮细胞存活，并通过诱导Ref-1/APE1依赖性血管生成以使缺血肢体重新血管化，从而为伴有过量ROS的CLI提供了一种有效的治疗方法。
