Modification of histones by the myeloperoxidase-derived oxidant hypochlorous acid (HOCl) alters their reactivity with vascular smooth muscle cells.

Els Alletta Hartsema, Line Amalie Egholm Hallberg, Kristine Alexandra Barlous, Clare Louise Hawkins

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Abstract

In the nucleus, histones are essential in the packaging of DNA and the regulation of gene expression. These
histones can also be released to the extracellular space by mechanisms such as necrosis and neutrophil extracellular trap (NET) formation. Histones are cytotoxic and cause sterile inflammation, and as a result, have been
implicated in tissue damage in several pathologies, including atherosclerosis. Myeloperoxidase (MPO) is also
present on NETs, which is catalytically active and able to produce hypochlorous acid (HOCl). This could modify
histones and alter their extracellular reactivity. In this study, we compared the reactivity of histones with and
without modification by HOCl with primary human coronary artery smooth muscle cells (HCASMCs). Histones
induced a loss in viability and cell death primarily by apoptosis, which was attenuated on modification of the
histones by HOCl. Exposure of HCASMCs to histones also resulted in the increased expression of the proinflammatory genes monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), and vascular cell
adhesion molecule-1 (VCAM-1) and a decrease in intracellular thiols. In addition, there were changes in the
expression of the stress related gene heme oxygenase-1 (HO-1). Modification of the histones with HOCl had no
significant influence on changes in gene expression or thiol loss, in contrast to the cytotoxicity studies. Together,
these studies provide new insight into the pathways by which histones could promote vascular dysfunction,
which could be relevant to inflammatory diseases, such as atherosclerosis and sepsis, which are associated with
elevated NET release and high circulating histones, respectively.
Original languageEnglish
Article number100010
JournalRedox Biochemistry and Biology
Volume5-6
Number of pages11
DOIs
Publication statusPublished - 2023

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