한빛사 논문
In-Su Parka,b,c,1, Chinmaya Mahapatraa,d,1,2, Ji Sun Parke, Khandmaa Dashnyama,d, Jong-Wan Kima, Jin Chul Ahnb,g,h, Phil-Sang Chungb,i, Dong Suk Yoona, Nandin Mandakhbayara,d, Rajendra K. Singha,d, Jung-Hwan Leea,j,k,*, Kam W. Leonge,f,*, Hae-Won Kima,d,j,k,*
a Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, South Korea
b Beckman Laser Institute Korea, Dankook University, Cheonan, 31116, South Korea
c Cell Therapy Center, Ajou University Medical Center, Suwon, South Korea
d Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, South Korea
e Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA
f Department of System Biology, Columbia University Medical Center, New York, NY, 10032, USA
g Department of Biomedical Science, Dankook University, Cheonan, 31116, South Korea
h Biomedical Translational Research Institute, Dankook University, Cheonan, 31116, South Korea
i Department of Otolaryngology-Head and Neck Surgery, Dankook University, Cheonan, 31116, South Korea
j Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116, South Korea
k UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, South Korea
*Corresponding author : Jung-Hwan Lee, Hae-Won Kim
1These authors contributed equally to this work.
2Current address: Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Helmholtz-Zentrum Geesthacht (HZG), Germany
Abstract
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.
Keywords
Critical limb ischemia; Pro-angiogenesis; Cerium oxide nanoparticle; Reactive oxygen species; Ref-1/APE1 pathway
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