Dataset Information

Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function.

ABSTRACT: Fibronectin (FN) occurs as both a soluble form, in plasma and at sites of tissue injury, and a cellular form in tissue extracellular matrices (ECM). FN is critical to wound repair, ECM structure and assembly, cell adhesion and proliferation. FN is reported to play a critical role in the development, progression and stability of cardiovascular atherosclerotic lesions, with high FN levels associated with a thick fibrotic cap, stable disease and a low risk of rupture. Evidence has been presented for FN modification by inflammatory oxidants, and particularly myeloperoxidase (MPO)-derived species including hypochlorous acid (HOCl). The targets and consequences of FN modification are poorly understood. Here we show, using a newly-developed MS protocol, that HOCl and an enzymatic MPO system, generate site-specific dose-dependent Tyr chlorination and dichlorination (up to 16 of 100 residues modified), and oxidation of Trp (7 of 39 residues), Met (3 of 26) and His (1 of 55) within selected FN domains, and particularly the heparin- and cell-binding regions. These alterations increase FN binding to heparin-containing columns. Studies using primary human coronary artery smooth muscle cells (HCASMC) show that exposure to HOCl-modified FN, results in decreased adherence, increased proliferation and altered expression of genes involved in ECM synthesis and remodelling. These findings indicate that the presence of modified fibronectin may play a major role in the formation, development and stabilisation of fibrous caps in atherosclerotic lesions and may play a key role in the switching of quiescent contractile smooth muscle cells to a migratory, synthetic and proliferative phenotype.

SUBMITTER: Nybo T

PROVIDER: S-EPMC6142189 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function.

Nybo Tina T Cai Huan H Chuang Christine Y CY Gamon Luke F LF Rogowska-Wrzesinska Adelina A Davies Michael J MJ

Redox biology 20180905

Fibronectin (FN) occurs as both a soluble form, in plasma and at sites of tissue injury, and a cellular form in tissue extracellular matrices (ECM). FN is critical to wound repair, ECM structure and assembly, cell adhesion and proliferation. FN is reported to play a critical role in the development, progression and stability of cardiovascular atherosclerotic lesions, with high FN levels associated with a thick fibrotic cap, stable disease and a low risk of rupture. Evidence has been presented fo ...[more]

PMID: 30237127

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Project description:Smooth muscle cells are maintained in a differentiated state in the vessel wall, but can be modulated to a synthetic phenotype following injury. Smooth muscle phenotypic modulation is thought to play an important role in the pathology of vascular occlusive diseases. Phenotypically modulated smooth muscle cells exhibit increased proliferative and migratory properties that accompany the downregulation of smooth muscle cell marker proteins. Extracellular matrix proteins, including fibronectin, can regulate the smooth muscle phenotype when used as adhesive substrates. However, cells produce and organize a 3-dimensional fibrillar extracellular matrix, which can affect cell behavior in distinct ways from the protomeric 2-dimensional matrix proteins that are used as adhesive substrates. We previously showed that the deposition/polymerization of fibronectin into the extracellular matrix can regulate the deposition and organization of other extracellular matrix molecules in vitro. Further, our published data show that the presence of a fibronectin polymerization inhibitor results in increased expression of smooth muscle cell differentiation proteins and inhibits vascular remodeling in vivo. In this manuscript, we used an in vitro cell culture system to determine the mechanism by which fibronectin polymerization affects smooth muscle phenotypic modulation. Our data show that fibronectin polymerization decreases the mRNA levels of multiple smooth muscle differentiation genes, and downregulates the levels of smooth muscle ?-actin and calponin proteins by a Rac1-dependent mechanism. The expression of smooth muscle genes is transcriptionally regulated by fibronectin polymerization, as evidenced by the increased activity of luciferase reporter constructs in the presence of a fibronectin polymerization inhibitor. Fibronectin polymerization also promotes smooth muscle cell growth, and decreases the levels of actin stress fibers. These data define a Rac1-dependent pathway wherein fibronectin polymerization promotes the SMC synthetic phenotype by modulating the expression of smooth muscle cell differentiation proteins.

Dataset Information

Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function.

Publications

Chlorination and oxidation of human plasma fibronectin by myeloperoxidase-derived oxidants, and its consequences for smooth muscle cell function.

Similar Datasets

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