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SHR Neuro Krebs Kardio Lipid

Bernhart, E; Kogelnik, N; Prasch, J; Gottschalk, B; Goeritzer, M; Depaoli, MR; Reicher, H; Nusshold, C; Plastira, I; Hammer, A; Fauler, G; Malli, R; Graier, WF; Malle, E; Sattler, W.
2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.
Redox Biol. 2018; 15: 441-451.
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Autor/innen der Med Uni Graz:
Bernhart Eva Maria
Fauler Günter
Göritzer Madeleine
Gottschalk Benjamin
Graier Wolfgang
Hammer Astrid
Kogelnik Nora
Malle Ernst
Malli Roland
Nusshold Christoph
Plastira Ioanna
Prasch Jürgen
Reicher Helga
Sattler Wolfgang
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Abstract:
Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system of activated phagocytes. HOCl targets the endogenous pool of ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic acid (2-ClHA). In the cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) that form the morphological basis of the BBB. To follow subcellular trafficking of 2-ClHA we synthesized a 'clickable' alkyne derivative (2-ClHyA) that phenocopied the biological activity of the parent compound. Confocal and superresolution structured illumination microscopy revealed accumulation of 2-ClHyA in the endoplasmic reticulum (ER) and mitochondria of human BMVEC (hCMEC/D3 cell line). 2-ClHA and its alkyne analogue interfered with protein palmitoylation, induced ER-stress markers, reduced the ER ATP content, and activated transcription and secretion of interleukin (IL)-6 as well as IL-8. 2-ClHA disrupted the mitochondrial membrane potential and induced procaspase-3 and PARP cleavage. The protein kinase R-like ER kinase (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating transcription factor 4 synthesis and IL-6/8 secretion, but showed no effect on endothelial barrier dysfunction and cleavage of procaspase-3. Our data indicate that 2-ClHA induces potent lipotoxic responses in brain endothelial cells and could have implications in inflammation-induced BBB dysfunction. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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