Anti-Inflammatory Effect of Targeted Delivery of SOD to Endothelium: Mechanism, Synergism with NO Donors and Protective Effects In Vitro and In Vivo

Vladimir V. Shuvaev, Jingyan Han, Samira Tliba, Evguenia Arguiri, Melpo Christofidou-Solomidou, Servio H. Ramirez, Holly Dykstra, Yuri Persidsky, Dmitriy N. Atochin, Paul L. Huang, Vladimir R. Muzykantov

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Pro-inflammatory activation of vascular endothelium is implicated in pathogenesis of severe conditions including stroke, infarction and sepsis. We have recently reported that superoxide dismutase (SOD) conjugated with antibodies (Ab/SOD) that provide targeted delivery into endothelial endosomes mitigates inflammatory endothelial activation by cytokines and agonists of Toll-like receptors (TLR). The goal of this study was to appraise potential utility and define the mechanism of this effect. Ab/SOD, but not non-targeted SOD injected in mice alleviated endotoxin-induced leukocyte adhesion in the cerebral vasculature and protected brain from ischemia-reperfusion injury. Transfection of endothelial cells with SOD, but not catalase inhibited NFκB signaling and expression of Vascular Cell Adhesion Molecule-1 induced by both cytokines and TLR agonists. These results affirmed that Ab/SOD-quenched superoxide anion produced by endothelial cells in response to proinflammatory agents mediates NFκB activation. Furthermore, Ab/SOD potentiates anti-inflammatory effect of NO donors in endothelial cells in vitro, as well as in the endotoxin-challenged mice. These results demonstrate the central role of intracellular superoxide as a mediator of pro-inflammatory activation of endothelium and support the notion of utility of targeted interception of this signaling pathway for management of acute vascular inflammation.

Original languageEnglish
Article numbere77002
JournalPLoS One
Volume8
Issue number10
DOIs
Publication statusPublished - 11 Oct 2013
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Fingerprint Dive into the research topics of 'Anti-Inflammatory Effect of Targeted Delivery of SOD to Endothelium: Mechanism, Synergism with NO Donors and Protective Effects In Vitro and In Vivo'. Together they form a unique fingerprint.

  • Cite this

    Shuvaev, V. V., Han, J., Tliba, S., Arguiri, E., Christofidou-Solomidou, M., Ramirez, S. H., Dykstra, H., Persidsky, Y., Atochin, D. N., Huang, P. L., & Muzykantov, V. R. (2013). Anti-Inflammatory Effect of Targeted Delivery of SOD to Endothelium: Mechanism, Synergism with NO Donors and Protective Effects In Vitro and In Vivo. PLoS One, 8(10), [e77002]. https://doi.org/10.1371/journal.pone.0077002