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https://hdl.handle.net/2440/117784
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Type: | Journal article |
Title: | Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca²⁺-ATPase activity and perturb Ca²⁺ homeostasis in human coronary artery endothelial cells |
Other Titles: | Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity and perturb Ca2+ homeostasis in human coronary artery endothelial cells |
Author: | Cook, N.L. Viola, H.M. Sharov, V.S. Hool, L.C. Schöneich, C. Davies, M.J. |
Citation: | Free Radical Biology and Medicine, 2012; 52(5):951-961 |
Publisher: | Elsevier |
Issue Date: | 2012 |
ISSN: | 0891-5849 1873-4596 |
Statement of Responsibility: | Naomi L. Cook, Helena M. Viola, Victor S. Sharov, Livia C. Hool, Christian Schöneich, Michael J. Davies |
Abstract: | The sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) plays a critical role in Ca²⁺ homeostasis via sequestration of this ion in the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in aging 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 preformed 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 concurrent 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 pretreatment 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 because of their higher SCN⁻ levels. |
Keywords: | Myeloperoxidase; calcium; oxidation; thiols; sarco/endoplasmic reticulum Ca²⁺-ATPase; SERCA; hypochlorous acid; hypothiocyanous acid; free radicals |
Rights: | © 2011 Elsevier Inc. All rights reserved. |
DOI: | 10.1016/j.freeradbiomed.2011.12.001 |
Grant ID: | NHMRC http://purl.org/au-research/grants/arc/CE0561607 http://purl.org/au-research/grants/arc/DP0988311 |
Published version: | http://dx.doi.org/10.1016/j.freeradbiomed.2011.12.001 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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