Low Concentrations of Oxidized Phospholipids Increase Stress Tolerance of Endothelial Cells
Christina Mauerhofer,
Taras Afonyushkin,
Olga V. Oskolkova,
Klara Hellauer,
Bernd Gesslbauer,
Jasmin Schmerda,
Yunbo Ke,
Andreas Zimmer,
Anna A. Birukova,
Konstantin G. Birukov,
Valery Bochkov
Affiliations
Christina Mauerhofer
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Taras Afonyushkin
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria
Olga V. Oskolkova
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Klara Hellauer
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Bernd Gesslbauer
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Jasmin Schmerda
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Yunbo Ke
Department of Anesthesiology, University of Maryland School of Medicine, 20 Penn. Street, HSF-2, Room 145, Baltimore, MD 21201, USA
Andreas Zimmer
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Universitätsplatz 1/EG, 8010 Graz, Austria
Anna A. Birukova
Department of Anesthesiology, University of Maryland School of Medicine, 20 Penn. Street, HSF-2, Room 145, Baltimore, MD 21201, USA
Konstantin G. Birukov
Department of Anesthesiology, University of Maryland School of Medicine, 20 Penn. Street, HSF-2, Room 145, Baltimore, MD 21201, USA
Valery Bochkov
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
Oxidized phospholipids (OxPLs) are generated by enzymatic or autooxidation of esterified polyunsaturated fatty acids (PUFAs) residues. OxPLs are present in circulation and atherosclerotic plaques where they are thought to induce predominantly proinflammatory and toxic changes in endothelial (ECs) and other cell types. Unexpectedly, we found that low concentrations of OxPLs were not toxic but protected ECs from stress induced by serum deprivation or cytostatic drugs. The protective effect was observed in ECs obtained from different vessels and was monitored using a variety of readouts based on different biological and chemical principles. Analysis of the structure–activity relationship identified oxidized or missing fatty acid residue (OxPLs or Lyso-PLs, respectively) as a prerequisite for the protective action of a PL. Protective OxPLs or Lyso-PLs acquired detergent-like properties and formed in solution aggregates 1000 nm, likely multilayer liposomes) produced by nonoxidized precursor PLs. Because surfactants, OxPLs, and Lyso-PLs are known to extract membrane cholesterol, we tested if this effect might trigger the protection of endothelial cells. The protective action of OxPLs and Lyso-PLs was inhibited by cotreatment with cholesterol and mimicked by cholesterol-binding beta-cyclodextrin but not inactive α-cyclodextrin. Wide-scale mRNA expression analysis in four types of ECs showed the induction of genes encoding for heat shock proteins (HSPs) and secreted prosurvival peptides and proteins. Inducers of HSPs, chemical chaperones, and pure prosurvival factors mimicked the protective action of OxPLs/Lyso-PLs. We hypothesize that oxidation changes the physicochemical properties of PLs, thus promoting membrane cholesterol redistribution or extraction leading to the expression of intra- and extracellular prosurvival factors.
