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Research ArticleCardiovascular

Catalase and Superoxide Dismutase Conjugated with Platelet-Endothelial Cell Adhesion Molecule Antibody Distinctly Alleviate Abnormal Endothelial Permeability Caused by Exogenous Reactive Oxygen Species and Vascular Endothelial Growth Factor

Jingyan Han, Vladimir V. Shuvaev and Vladimir R. Muzykantov
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 82-91; DOI: https://doi.org/10.1124/jpet.111.180620
Jingyan Han
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Vladimir V. Shuvaev
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Vladimir R. Muzykantov
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Abstract

Reactive oxygen species (ROS) superoxide anion (O2⨪) and hydrogen peroxide (H2O2) produced by activated leukocytes and endothelial cells in sites of inflammation or ischemia cause endothelial barrier dysfunction that may lead to tissue edema. Antioxidant enzymes (AOEs) catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically bind to endothelium, quench the corresponding ROS, and alleviate vascular oxidative stress and inflammation. In the present work, we studied the effects of anti-PECAM/catalase and anti-PECAM/SOD conjugates on the abnormal permeability manifested by transendothelial electrical resistance decline, increased fluorescein isothiocyanate-dextran influx, and redistribution of vascular endothelial-cadherin in human umbilical vein endothelial cell (HUVEC) monolayers. Anti-PECAM/catalase protected HUVEC monolayers against H2O2-induced endothelial barrier dysfunction. Polyethylene glycol-conjugated catalase exerted orders of magnitude lower endothelial uptake and no protective effect, similarly to IgG/catalase. Anti-PECAM/catalase, but not anti-PECAM/SOD, alleviated endothelial hyperpermeability caused by exposure to hypoxanthine/xanthine oxidase, implicating primarily H2O2 in the disruption of the endothelial barrier in this model. Thrombin-induced endothelial permeability was not affected by treatment with anti-PECAM/AOEs or the NADPH oxidase inhibitor apocynin or overexpression of AOEs, indicating that the endogenous ROS play no key role in thrombin-mediated endothelial barrier dysfunction. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase, inhibited a vascular endothelial growth factor (VEGF)-induced increase in endothelial permeability, identifying a key role of endogenous O2⨪ in the VEGF-mediated regulation of endothelial barrier function. Therefore, AOEs targeted to endothelial cells provide versatile molecular tools for testing the roles of specific ROS in vascular pathology and may be translated into remedies for these ROS-induced abnormalities.

Footnotes

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL073940] (to V.R.M.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180620.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    VEGF
    vascular endothelial growth factor
    ROS
    reactive oxygen species
    AOE
    antioxidant enzyme
    SOD
    superoxide dismutase
    PECAM-1
    platelet-endothelial cell adhesion molecule-1
    PEG
    polyethylene glycol
    NOX
    NADPH oxidase
    HUVEC
    human umbilical vein endothelial cell
    VE
    vascular endothelial
    HX
    hypoxanthine
    XO
    xanthine oxidase
    NO
    nitric oxide
    Ab
    antibody
    ELISA
    enzyme-linked immunosorbent assay
    DPI
    diphenylene iodonium
    FITC
    fluorescein isothiocyanate
    TEER
    transendothelial electrical resistance
    HBSS
    Hanks' balanced salt solution.

  • Received February 16, 2011.
  • Accepted April 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleCardiovascular

Catalase and Superoxide Dismutase Conjugated with Platelet-Endothelial Cell Adhesion Molecule Antibody Distinctly Alleviate Abnormal Endothelial Permeability Caused by Exogenous Reactive Oxygen Species and Vascular Endothelial Growth Factor

Jingyan Han, Vladimir V. Shuvaev and Vladimir R. Muzykantov
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 82-91; DOI: https://doi.org/10.1124/jpet.111.180620

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Research ArticleCardiovascular

Catalase and Superoxide Dismutase Conjugated with Platelet-Endothelial Cell Adhesion Molecule Antibody Distinctly Alleviate Abnormal Endothelial Permeability Caused by Exogenous Reactive Oxygen Species and Vascular Endothelial Growth Factor

Jingyan Han, Vladimir V. Shuvaev and Vladimir R. Muzykantov
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 82-91; DOI: https://doi.org/10.1124/jpet.111.180620
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