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Degendorfer, G; Chuang, CY; Hammer, A; Malle, E; Davies, MJ.
Peroxynitrous acid induces structural and functional modifications to basement membranes and its key component, laminin.
Free Radic Biol Med. 2015; 89(48):721-733
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Autor/innen der Med Uni Graz:
Hammer Astrid
Malle Ernst

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Basement membranes (BM) are specialized extracellular matrices underlying endothelial cells in the artery wall. Laminin, the most abundant BM glycoprotein, is a structural and biologically active component. Peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent, is formed in vivo at sites of inflammation from superoxide and nitric oxide radicals. Considerable data supports ONOOH formation in human atherosclerotic lesions, and an involvement of this oxidant in atherosclerosis development and lesion rupture. These effects may be mediated, at least in part, via extracellular matrix damage. In this study we demonstrate co-localization of 3-nitrotyrosine (a product of tyrosine damage by ONOOH) and laminin in human atherosclerotic lesions. ONOOH-induced damage to BM was characterized for isolated murine BM, and purified murine laminin-111. Exposure of laminin-111 to ONOOH resulted in dose-dependent loss of protein tyrosine and tryptophan residues, and formation of 3-nitrotyrosine, 6-nitrotryptophan and the cross-linked material di-tyrosine, as detected by amino acid analysis and Western blotting. These changes were accompanied by protein aggregation and fragmentation as detected by SDS-PAGE. Endothelial cell adhesion to isolated laminin-111 exposed to 10 μM or higher levels of ONOOH was significantly decreased (~25%) compared to untreated controls. These data indicate that laminin is oxidized by equimolar or greater concentrations of ONOOH, with this resulting in structural and functional changes. These modifications, and resulting compromised cell-matrix interactions, may contribute to endothelial cell dysfunction, a weakening of the structure of atherosclerotic lesions, and an increased propensity to rupture. Copyright © 2015 Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Atherosclerosis - metabolism
Atherosclerosis - pathology
Basement Membrane - pathology
Blotting, Western -
Cells, Cultured -
Chromatography, High Pressure Liquid -
Electrophoresis, Polyacrylamide Gel -
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Enzyme-Linked Immunosorbent Assay -
Extracellular Matrix -
Humans -
Immunohistochemistry -
Laminin - metabolism
Mice -
Microscopy, Confocal -
Oxidants - metabolism
Oxidants - pharmacology
Oxidation-Reduction -
Peroxynitrous Acid - metabolism
Peroxynitrous Acid - pharmacology

Find related publications in this database (Keywords)
Extracellular matrix
Peroxynitrous acid
Protein oxidation
Endothelial cells
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