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Redox Biol. 2018 May;15:441-451. doi: 10.1016/j.redox.2018.01.003. Epub 2018 Jan 5.

2-Chlorohexadecanoic acid induces ER stress and mitochondrial dysfunction in brain microvascular endothelial cells.

Author information

1
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: eva.bernhart@medunigraz.at.
2
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: nora.kogelnik@medunigraz.at.
3
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: j.prasch@medunigraz.at.
4
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: benjamin.gottschalk@medunigraz.at.
5
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria; BioTechMed Graz, Austria. Electronic address: madeleine.goeritzer@medunigraz.at.
6
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: m.depaoli@medunigraz.at.
7
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: helga.reicher@medunigraz.at.
8
Institute of Physiological Chemistry, Medical University of Graz, Austria. Electronic address: christoph.nusshold@medunigraz.at.
9
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: ioanna.plastira@medunigraz.at.
10
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Cell Biology, Histology and Embryology, Medical University of Graz, Austria. Electronic address: astrid.hammer@medunigraz.at.
11
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria. Electronic address: guenter.fauler@medunigraz.at.
12
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria; BioTechMed Graz, Austria. Electronic address: roland.malli@medunigraz.at.
13
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria; BioTechMed Graz, Austria. Electronic address: wolfgang.graier@medunigraz.at.
14
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: ernst.malle@medunigraz.at.
15
Gottfried Schatz Research Center for Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria; BioTechMed Graz, Austria. Electronic address: wolfgang.sattler@medunigraz.at.

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.

KEYWORDS:

Apoptosis; Blood-brain barrier; Lipotoxicity; Myeloperoxidase; Neuroinflammation; Structured illumination microscopy

PMID:
29413957
PMCID:
PMC5975063
DOI:
10.1016/j.redox.2018.01.003
[Indexed for MEDLINE]
Free PMC Article

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