Role of myeloperoxidase-derived oxidants in the induction of vascular smooth muscle cell damage

Flouda, K., Mercer, J. , Davies, M. J. and Hawkins, C. L. (2021) Role of myeloperoxidase-derived oxidants in the induction of vascular smooth muscle cell damage. Free Radical Biology and Medicine, 166, pp. 165-177. (doi: 10.1016/j.freeradbiomed.2021.02.021) (PMID:33631301)

Abstract

Myeloperoxidase (MPO) is released by activated immune cells and forms the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) from the competing substrates chloride and thiocyanate. MPO and the overproduction of HOCl are strongly linked with vascular cell dysfunction and inflammation in atherosclerosis. HOCl is highly reactive and causes marked cell dysfunction and death, whereas data with HOSCN are conflicting, and highly dependent on the nature of the cell type. In this study we have examined the reactivity of HOCl and HOSCN with human coronary artery smooth muscle cells (HCASMC), given the key role of this cell type in maintaining vascular function. HOCl reacts rapidly with the cells, resulting in extensive cell death by both necrosis and apoptosis, and increased levels of intracellular calcium. In contrast, HOSCN reacts more slowly, with cell death occurring only after prolonged incubation, and in the absence of the accumulation of intracellular calcium. Exposure of HCASMC to HOCl also influences mitochondrial respiration, decreases glycolysis, lactate release, the production of ATP, cellular thiols and glutathione levels. These changes occurred to varying extents on exposure of the cells to HOSCN, where evidence was also obtained for the reversible modification of cellular thiols. HOCl also induced alterations in the mRNA expression of multiple inflammatory and phenotypic genes. Interestingly, the extent and nature of these changes was highly dependent on the specific cell donor used, with more marked effects observed in cells isolated from diseased compared to healthy vessels. Overall, these data provide new insight into pathways promoting vascular dysfunction during chronic inflammation, support the use of thiocyanate as a means to modulate MPO-induced cellular damage in atherosclerosis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Flouda, Konstantina and Mercer, Dr John
• Authors: Flouda, K., Mercer, J., Davies, M. J., and Hawkins, C. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Free Radical Biology and Medicine
• Publisher: Elsevier
• ISSN: 0891-5849
• ISSN (Online): 1873-4596
• Published Online: 22 February 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Free Radical Biology and Medicine 166:165-177
• Publisher Policy: Reproduced under a Creative Commons licence