Exposure to peroxynitrite impacts the ability of anastellin to modulate the structure of extracellular matrix

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Abstract

The extracellular matrix (ECM) of tissues consists of multiple proteins, proteoglycans and glycosaminoglycans that form a 3-dimensional meshwork structure. This ECM is exposed to oxidants including peroxynitrite (ONOO/ONOOH) generated by activated leukocytes at sites of inflammation. Fibronectin, a major ECM protein targeted by peroxynitrite, self-assembles into fibrils in a cell-dependent process. Fibrillation of fibronectin can also be initiated in a cell-independent process in vitro by anastellin, a recombinant fragment of the first type-III module in fibronectin. Previous studies demonstrated that modification of anastellin by peroxynitrite impairs its fibronectin polymerization activity. We hypothesized that exposure of anastellin to peroxynitrite would also impact on the structure of ECM from cells co-incubated with anastellin, and influence interactions with cell surface receptors. Fibronectin fibrils in the ECM of primary human coronary artery smooth muscle cells exposed to native anastellin are diminished, an effect which is reversed to a significant extent by pre-incubation of anastellin with high (200-fold molar excess) concentrations of peroxynitrite. Treatment with low or moderate levels of peroxynitrite (2–20 fold molar excess) influences interactions between anastellin and heparin polysaccharides, as a model of cell-surface proteoglycan receptors, and modulates anastellin-mediated alterations in fibronectin cell adhesiveness. Based on these observations it is concluded that peroxynitrite has a dose-dependent influence on the ability of anastellin to modulate ECM structure via interactions with fibronectin and other cellular components. These observations may have pathological implications since alterations in fibronectin processing and deposition have been associated with several pathologies, including atherosclerosis.

OriginalsprogEngelsk
TidsskriftFree Radical Biology and Medicine
Vol/bind206
Sider (fra-til)83-93
Antal sider11
ISSN0891-5849
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This work was supported by the Novo Nordisk Foundation (Laureate grants: NNF13OC0004294 and NNF20SA0064214 to MJD), the Danish Council for Independent Research | Natural Sciences ( DFF-7014-00047 to MJD), and the China Scholarship Council (scholarship to Jianfei He).

Publisher Copyright:
© 2023 The Authors

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