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Vanichkitrungruang, S; Chuang, CY; Hawkins, CL; Hammer, A; Hoefler, G; Malle, E; Davies, MJ.
Oxidation of human plasma fibronectin by inflammatory oxidants perturbs endothelial cell function.
Free Radic Biol Med. 2019; 136(Suppl 1): 118-134. Doi: 10.1016/j.freeradbiomed.2019.04.003
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Co-Autor*innen der Med Uni Graz
Hammer Astrid
Höfler Gerald
Malle Ernst
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Abstract:
Dysfunction of endothelial cells of the artery wall is an early event in cardiovascular disease and atherosclerosis. The cause(s) of this dysfunction are unresolved, but accumulating evidence suggests that oxidants arising from chronic low-grade inflammation are contributory agents, with increasing data implicating myeloperoxidase (MPO, released by activated leukocytes), and the oxidants it generates (e.g. HOCl and HOSCN). As these are formed extracellularly and react rapidly with proteins, we hypothesized that MPO-mediated damage to the matrix glycoprotein fibronectin (FN) would modulate FN structure and function, and its interactions with human coronary artery endothelial cells (HCAEC). Exposure of human plasma FN to HOCl resulted in modifications to FN and its functional epitopes. A dose-dependent loss of methionine and tryptophan residues, together with increasing concentrations of methionine sulfoxide, and modification of the cell-binding fragment (CBF) and heparin-binding fragment (HBF) domains was detected with HOCl, but not HOSCN. FN modification resulted in a loss of HCAEC adhesion, impaired cell spreading and reduced cell proliferation. Exposure to HCAEC to HOCl-treated FN altered the expression of HCAEC genes associated with extracellular matrix (ECM) synthesis and adhesion. Modifications were detected on HCAEC-derived ECM pre-treated with HOCl, but not HOSCN, with a loss of antibody recognition of the CBF, HBF and extra-domain A. Co-localization of epitopes arising from MPO-generated HOCl and cell-derived FN was detected in human atherosclerotic lesions. Damage was also detected on FN extracted from lesions. These data support the hypothesis that HOCl, but not HOSCN, targets and modifies FN resulting in arterial wall endothelial cell dysfunction. Copyright © 2019. Published by Elsevier Inc.

Find related publications in this database (Keywords)
Extracellular matrix
Hypochlorous acid
Myeloperoxidase
Hypothiocyanous acid
Fibronectin
Protein oxidation
Endothelial cell
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