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

被引：33

作者：

Bernhart, Eva ^{[1
]}

Kogelnik, Nora ^{[1
]}

Prasch, Juergen ^{[1
]}

Gottschalk, Benjamin ^{[1
]}

Goeritzer, Madeleine ^{[1
,2
]}

Depaoli, Maria Rosa ^{[1
]}

Reicher, Helga ^{[1
]}

Nusshold, Christoph ^{[3
]}

Plastira, Ioanna ^{[1
]}

Hammer, Astrid ^{[4
]}

Fauler, Guenter ^{[5
]}

Malli, Roland ^{[1
,2
]}

Graier, Wolfgang F. ^{[1
,2
]}

Malle, Ernst ^{[1
]}

Sattler, Wolfgang ^{[1
,2
]}

机构：

[1] Med Univ Graz, Gottfried Schatz Res Ctr Signaling Metab & Aging, Mol Biol & Biochem, Graz, Austria

[2] BioTechMed Graz, Graz, Austria

[3] Med Univ Graz, Inst Physiol Chem, Graz, Austria

[4] Med Univ Graz, Gottfried Schatz Res Ctr Signaling Metab & Aging, Cell Biol Histol & Embryol, Graz, Austria

[5] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria

来源：

REDOX BIOLOGY | 2018年 / 15卷

基金：

奥地利科学基金会;

关键词：

Apoptosis; Blood-brain barrier; Lipotoxicity; Myeloperoxidase; Neuroinflammation; Structured illumination microscopy; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; HIGH-DENSITY-LIPOPROTEIN; OXIDATIVE STRESS; BACTERIAL-MENINGITIS; ALZHEIMERS-DISEASE; MYELOPEROXIDASE; BARRIER; PALMITOYLATION; PLASMALOGENS;

D O I：

10.1016/j.redox.2018.01.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. HOCI 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-CIHA 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.

引用

页码：441 / 451

页数：11

共 68 条

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