Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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"Köpfe" der aktuellen Meldungen:

Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

Gerhard Pichler

Roland Malli

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Degendorfer, G; Chuang, CY; Kawasaki, H; Hammer, A; Malle, E; Yamakura, F; Davies, MJ.
Peroxynitrite-mediated oxidation of plasma fibronectin.
Free Radic Biol Med. 2016; 97(3):602-615 Doi: 10.1016/j.freeradbiomed.2016.06.013
Web of Science PubMed FullText FullText_MUG

Co-Autor*innen der Med Uni Graz: Hammer Astrid; Malle Ernst
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Abstract:: Fibronectin is a large dimeric glycoprotein present in both human plasma and in basement membranes. The latter are specialized extracellular matrices underlying endothelial cells in the artery wall. Peroxynitrous acid (ONOOH) a potent oxidizing and nitrating agent, is formed in vivo from superoxide and nitric oxide radicals by stimulated macrophages and other cells. Considerable evidence supports ONOOH involvement in human atherosclerotic lesion development and rupture, possibly via extracellular matrix damage. Here we demonstrate that Tyr and Trp residues on human plasma fibronectin are highly sensitive to ONOOH with this resulting in the formation of 3-nitrotyrosine, 6-nitrotryptophan and dityrosine as well as protein aggregation and fragmentation. This occurs with equimolar or greater levels of oxidant, and in a dose-dependent manner. Modification of Tyr was quantitatively more significant than Trp (9.1% versus 1.5% conversion with 500μM ONOOH) after accounting for parent amino acid abundance, but only accounts for a small percentage of the total oxidant added. LC-MS studies identified 28 nitration sites (24 Tyr, 4 Trp) with many of these present within domains critical to protein function, including the cell-binding and anastellin domains. Human coronary artery endothelial cells showed decreased adherence and cell-spreading on ONOOH-modified fibronectin compared to control, consistent with cellular dysfunction induced by the modified matrix. Studies on human atherosclerotic lesions have provided evidence for co-localization of 3-nitrotyrosine and fibronectin. ONOOH-mediated fibronectin modification and compromised cell-matrix interactions, may contribute to endothelial cell dysfunction, a weakening of the fibrous cap of atherosclerotic lesions, and an increased propensity to rupture. Copyright © 2016 Elsevier B.V. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing): Amino Acid Sequence -; Atherosclerosis - metabolism; Atherosclerosis - pathology; Carotid Arteries - metabolism; Carotid Arteries - pathology; Cell Adhesion -; Cells, Cultured -; Endothelial Cells - physiology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Fibronectins - chemistry; Fibronectins - metabolism; Humans -; Nitrates - chemistry; Oxidants - chemistry; Oxidation-Reduction -; Peroxynitrous Acid - chemistry
Find related publications in this database (Keywords): Extracellular matrix; Peroxynitrite; Peroxynitrous acid; Fibronectin; Protein oxidation; 3-Nitrotyrosine; Dityrosine