title: Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro.
abstract: 2-Chlorohexadecanal (2-ClHDA), a chlorinated fatty aldehyde, is formed via attack on ether-phospholipids by hypochlorous acid (HOCl) that is generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated leukocytes. 2-ClHDA levels are elevated in atherosclerotic lesions, myocardial infarction, and neuroinflammation. Neuroinflammatory conditions are accompanied by accumulation of neutrophils (an ample source of myeloperoxidase) in the brain. Microvessel damage by inflammatory mediators and/or reactive oxidants can induce blood-brain barrier (BBB) dysfunction, a pathological condition leading to cerebral edema, brain hemorrhage, and neuronal death. In this in vitro study we investigated the impact of 2-ClHDA on brain microvascular endothelial cells (BMVEC), which constitute the morphological basis of the BBB. We show that exogenously added 2-ClHDA is subject to rapid uptake and metabolism by BMVEC. Using C16 structural analogues of 2-ClHDA we found that the cytotoxic potential decreases in the following order: 2-ClHDA>hexadecanal>palmitic acid>2-ClHDA-dimethylacetal. 2-ClHDA induces loss of barrier function, mitochondrial dysfunction, apoptosis via activation of caspase 3, and altered intracellular redox balance. Finally we investigated potential protective effects of several natural polyphenols on in vitro BBB function. Of the compounds tested, phloretin almost completely abrogated 2-ClHDA-induced BMVEC barrier dysfunction and cell death. These data suggest that 2-ClHDA has the potential to induce BBB breakdown under inflammatory conditions and that phloretin confers protection in this experimental setting.
authors.affiliation: Institute of Molecular Biology and Biochemistry, University Children's Hospital, Medical University of Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ullen
authors.forename: Günter
authors.initials: G
authors.lastname: Fauler
authors.forename: Eva
authors.initials: E
authors.lastname: Bernhart
authors.forename: Christoph
authors.initials: C
authors.lastname: Nusshold
authors.forename: Helga
authors.initials: H
authors.lastname: Reicher
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Leis
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
mesh_terms: D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D002199:Capillary Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D007700:Kinetics; D055806:Microvessels / Q000166:cytology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D010693:Phloretin / Q000494:pharmacology*; D010695:Phlorhizin / Q000494:pharmacology; D061251:Primary Cell Culture; D013552:Swine
chemical_list: C432398:2-chlorohexadecanal; D000447:Aldehydes; D019308:Palmitic Acid; D010695:Phlorhizin; D010693:Phloretin