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dc.contributor.authorCook, Naomi L.
dc.contributor.authorViola, Helena M.
dc.contributor.authorSharov, Victor S.
dc.contributor.authorHool, Livia C.
dc.contributor.authorSchoeneich, Christian
dc.contributor.authorDavies, Michael J.
dc.date.accessioned2017-03-09T21:46:27Z
dc.date.available2017-03-09T21:46:27Z
dc.date.issued2013-08-07
dc.identifier.citationCook, Naomi L., Helena M. Viola, Victor S. Sharov, Livia C. Hool, Christian Schöneich, and Michael J. Davies. "Myeloperoxidase-derived Oxidants Inhibit Sarco/endoplasmic Reticulum Ca2 -ATPase Activity and Perturb Ca2 Homeostasis in Human Coronary Artery Endothelial Cells." Free Radical Biology and Medicine 52.5 (2012): 951-61.en_US
dc.identifier.urihttp://hdl.handle.net/1808/23392
dc.description.abstractThe sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) plays a critical role in Ca2+ homeostasis via sequestration of this ion into the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in ageing tissues and cardiovascular disease. We have shown previously that the myeloperoxidase- (MPO) derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca2+ levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to pre-formed or enzymatically-generated HOCl and HOSCN resulted in a concentration-dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrently with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca2+, to HOSCN or HOCl, resulted in a time- and concentration-dependent increase in intracellular Ca2+ under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca2+ pumps/channels, completely attenuated the increase in intracellular Ca2+ consistent with a critical role for SERCA in maintaining endothelial cell Ca2+ homeostasis. Angiotensin II pre-treatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca2+ levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers due to their higher SCN− levels.en_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subjectMyeloperoxidaseen_US
dc.subjectCalciumen_US
dc.subjectOxidationen_US
dc.subjectThiolsen_US
dc.subjectSarco/endoplasmic reticulum Ca2+-ATPase (SERCA)en_US
dc.subjectHypochlorous aciden_US
dc.subjectHypothiocyanous aciden_US
dc.titleMyeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity, and perturb Ca2+ homeostasis in human coronary artery endothelial cellsen_US
dc.typeArticleen_US
kusw.kuauthorSchoeneich, Christian
kusw.kudepartmentPharmaceutical Chemistryen_US
dc.identifier.doi10.1016/j.freeradbiomed.2011.12.001en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.