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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 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bernhart Eva Maria
Depaoli Maria Rosa
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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Number of Figures: 8
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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.

Find related publications in this database (Keywords)
Apoptosis
Blood-brain barrier
Lipotoxicity
Myeloperoxidase
Neuroinflammation
Structured illumination microscopy
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