Comparative reactivity of the myeloperoxidase-derived oxidants hypochlorous acid and hypothiocyanous acid with human coronary artery endothelial cells

Research output: Contribution to journalJournal articleResearchpeer-review

Mitchell M Lloyd, Michael A Grima, Benjamin S Rayner, Katrina A Hadfield, Michael Jonathan Davies, Clare Louise Hawkins

In the immune response, hypohalous acids are generated by activated leukocytes via the release of myeloperoxidase and the formation of H2O2. Although these oxidants have important bactericidal properties, they have also been implicated in causing tissue damage in inflammatory diseases, including atherosclerosis. Hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) are the major oxidants formed by myeloperoxidase under physiological conditions, with the ratio of these oxidants dependent on diet and smoking status. HOCl is highly reactive and causes marked cellular damage, but few data are available on the effects of HOSCN on mammalian cells. In this study, we have compared the actions of HOCl and HOSCN on human coronary artery endothelial cells (HCAEC). HOCl reacts rapidly with the cells, resulting in extensive cell death by both apoptosis and necrosis, with necrosis dominating at higher oxidant doses. In contrast, HOSCN is consumed more slowly, with cell death occurring only by apoptosis. Exposure of HCAEC to HOCl and HOSCN induces changes in mitochondrial membrane permeability, which, in the case of HOSCN, is associated with mitochondrial release of proapoptotic factors, including cytochrome c, apoptosis-inducing factor, and endonuclease G. With each oxidant, apoptosis appears to be caspase-independent, with the inactivation of caspases 3/7 observed, and pretreatment of the cells with the caspase inhibitor Z-VAD-fmk having no effect on the extent of cell death. Loss of cellular thiols, depletion of glutathione, and the inactivation of thiol-dependent enzymes, including glyceraldehyde-3-phosphate dehydrogenase, were seen with both oxidants, though to a much greater extent with HOCl. The ability of myeloperoxidase-derived oxidants to induce endothelial cell apoptosis may contribute to the formation of unstable lesions in atherosclerosis. The results with HOSCN may be particularly significant for smokers, who have elevated plasma levels of SCN(-), the precursor of this oxidant.

Original languageEnglish
JournalFree Radical Biology & Medicine
Volume65
Pages (from-to)1352-62
Number of pages11
ISSN0891-5849
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

    Research areas

  • Amino Acid Chloromethyl Ketones, Apoptosis, Apoptosis Inducing Factor, Atherosclerosis, Caspase 3, Caspase 7, Caspase Inhibitors, Cell Line, Cell Survival, Coronary Vessels, Cytochromes c, Endodeoxyribonucleases, Endothelial Cells, Glutathione, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Humans, Hydrogen Peroxide, Hypochlorous Acid, Mitochondrial Membranes, Necrosis, Oxidation-Reduction, Permeability, Peroxidase, Sulfhydryl Compounds, Thiocyanates

ID: 128974109