title: 7-Ketocholesterol and 5,6-secosterol induce human endothelial cell dysfunction by differential mechanisms.
abstract: 7-Ketocholesterol and 5,6-secosterol are cholesterol autoxidation products generated under oxidative stress by two distinct mechanisms. They are present in atherosclerotic plaques and are candidate players in the disease initiation and progression. While 7-ketocholesterol affects at cellular level, in particular apoptosis, are well known and reported on diverse cell lines, 5,6-secosterol is a recently discovered oxysterol with relatively few reports on the potential to affect endothelial cell functions. Endothelial cells have a central role in cardiovascular disease as they provide the barrier between blood and the vessel wall where atherosclerosis starts and progresses. Insults to endothelial cells provoke their dysfunction favoring pro-atherogenic and pro-thrombotic effects. In the present work, we tested 7-ketocholesterol and 5,6-secosterol on endothelial cells - focusing on apoptosis and the associated mitochondrial/lysosome alterations - and on endothelial function using the in vitro model of arterial relaxation of aortic rings. Our data provide evidence that 7-ketocholesterol and 5,6-secosterol are efficient instigators of apoptosis, which for 5,6-secosterol is associated to PKC and p53 up-regulation. In addition 5,6-secosterol is a potent inhibitor of endothelial-dependent arterial relaxation through PKC-dependent mechanisms. This may contribute to pro-atherogenic and pro-thrombotic mechanisms of 5,6-secosterol and highlights the role of cholesterol autoxidation in cardiovascular disease.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy. Electronic address: francesca.luchetti@uniurb.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Luchetti
authors.affiliation: Department of Earth, Life and Environmental Science, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Canonico
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Cesarini
authors.affiliation: Department of Earth, Life and Environmental Science, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Betti
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Galluzzi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Galli
authors.affiliation: Division of Cell & Molecular Biology, Biochemistry Building, Imperial College, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Tippins
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies Vascular Biology, Atherothrombosis & Mass Spectrometry, Sapienza University of Rome, Latina, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zerbinati
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Papa
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies Vascular Biology, Atherothrombosis & Mass Spectrometry, Sapienza University of Rome, Latina, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D002308:Cardiolipins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007653:Ketocholesterols / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011419:Propidium / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling; D013261:Sterols / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C479527:5,6-secosterol; D017304:Annexin A5; D002308:Cardiolipins; D007653:Ketocholesterols; D013261:Sterols; D011419:Propidium; C003001:7-ketocholesterol
keywords: 5,6-Secosterol; 7-Ketocholesterol; Apoptosis; Endothelial dysfunction; HUVEC; Oxysterols