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

摘要: Abstract Peripheral leukocytes induce blood-brain barrier (BBB) dysfunction through the release of cytotoxic mediators. These include hypochlorous acid (HOCl) that is formed via myeloperoxidase-H 2 O -chloride system activated phagocytes. HOCl targets endogenous pool ether phospholipids (plasmalogens) generating chlorinated inflammatory mediators like e.g. 2-chlorohexadecanal and its conversion product 2-chlorohexadecanoic (2-ClHA). In cerebrovasculature these compounds inflict damage to brain microvascular endothelial cells (BMVEC) form morphological basis BBB. To follow subcellular trafficking 2-ClHA we synthesized a ‘clickable’ alkyne derivative (2-ClHyA) phenocopied biological activity parent compound. Confocal superresolution structured illumination microscopy revealed accumulation 2-ClHyA in endoplasmic reticulum (ER) mitochondria human BMVEC (hCMEC/D3 cell line). analogue interfered with protein palmitoylation, induced ER-stress markers, reduced ER ATP content, transcription secretion interleukin (IL)−6 as well IL-8. disrupted mitochondrial membrane potential procaspase-3 PARP cleavage. The kinase R-like (PERK) inhibitor GSK2606414 suppressed 2-ClHA-mediated activating factor 4 synthesis IL-6/8 secretion, but showed no effect on cleavage procaspase-3. Our data indicate induces potent lipotoxic responses could have implications inflammation-induced BBB dysfunction.