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CORM-401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells.

Kaczara, P; Proniewski, B; Lovejoy, C; Kuś, K; Motterlini, R; Abramov, AY; Chlopicki, S; (2018) CORM-401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells. The FEBS Journal , 285 (7) pp. 1346-1358. 10.1111/febs.14411. Green open access

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Abstract

Carbon monoxide-releasing molecules (CO-RMs) induce nitric oxide (NO) release (which requires NADPH), and Ca2+-dependent signalling; however, their contribution in mediating endothelial responses is not clear. Here, we studied the effects of CO liberated from CORM-401 on NO production, calcium signalling and pentose phosphate pathway (PPP) activity in human endothelial cell line (EA.hy926). CORM-401 induced NO production and two types of calcium signalling: a peak-like calcium signal and a gradual increase in cytosolic calcium. CORM-401-induced peak-like calcium signal, originating from endoplasmic reticulum, was reduced by thapsigargin, a SERCA inhibitor, and by dantrolene, a ryanodine receptors (RyR) inhibitor. In contrast, the phospholipase C (PLC) inhibitor U73122 did not significantly affect peak-like calcium signalling, but a slow and progressive CORM-401-induced increase in cytosolic calcium was dependent on store-operated calcium entrance. CORM-401 augmented coupling of endoplasmic reticulum and plasmalemmal store-operated calcium channels (SOC). Interestingly, in the presence of NO synthase inhibitor (L-NAME) CORM-401-induced increases in NO and cytosolic calcium were both abrogated. CORM-401-induced calcium signalling was also inhibited by superoxide dismutase (PEG-SOD). Furthermore, CORM-401 accelerated PPP, increased NADPH concentration and decreased the ratio of reduced to oxidized glutathione (GSH/GSSG). Importantly, CORM-401-induced NO increase was inhibited by the PPP inhibitor 6-aminonicotinamide (6-AN), but neither by dantrolene nor by an inhibitor of large-conductance calcium-regulated potassium ion channel (paxilline). The results identify the primary role of CO-induced NO increase in the regulation of endothelial calcium signalling, that may have important consequences in controlling endothelial function. This article is protected by copyright. All rights reserved.

Type: Article
Title: CORM-401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/febs.14411
Publisher version: http://dx.doi.org/10.1111/febs.14411
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: NADPH, Calcium, Carbon Monoxide, Endothelium, Nitric Oxide, Pentose Phosphate Pathway, Ryanodine Receptor
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/10044516
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