title: Plasma-derived and synthetic high-density lipoprotein inhibit tissue factor in endothelial cells and monocytes.
abstract: HDL (high-density lipoproteins) exert anti-thrombotic activities by preventing platelet adhesion and activation and by stimulating the protein C pathway and fibrinolysis. The aim of the present study was to assess the effect of plasma-derived and synthetic HDL on endothelial and monocyte expression of TF (tissue factor), the primary initiator of coagulation. HDL inhibited TF expression and activity in stimulated endothelial cells and monocytes in a dose-dependent way. Synthetic HDL fully retain the ability to inhibit TF expression in a dose-dependent manner; lipid-free apoA-I (apolipoprotein A-I) was not effective and neither was sphingosine 1-phosphate involved. HDL-mediated TF inhibition was due to a modulation of cellular cholesterol content through the interaction with SR-BI (scavenger receptor BI); downstream, HDL inhibited the activation of p38 MAPK (mitogen-activated protein kinase) and the repression of the PI3K (phosphoinositide 3-kinase) pathway responsible for TF expression. In vivo, human apoA-I-transgenic mice displayed a reduced aortic TF expression compared with wild-type animals and TF plasma levels were increased in subjects with low HDL-C (HDL-cholesterol) levels compared with high HDL-C subjects. Thus the anti-thrombotic activity of HDL could also be mediated by the inhibition of TF expression and activity in endothelial cells and monocytes; synthetic HDL retain the inhibitory activity of plasma-derived HDL, supporting the hypothesis that synthetic HDL infusion may be beneficial in the setting of acute coronary syndrome.
authors.affiliation: Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy Lipoprotein Metabolism Section, NHLBI, NIH, Bethesda, MD 20814, U.S.A.
authors.forename: Alice
authors.initials: A
authors.lastname: Ossoli
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, NIH, Bethesda, MD 20814, U.S.A.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Lipoprotein Metabolism Section, NHLBI, NIH, Bethesda, MD 20814, U.S.A.
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.affiliation: Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy laura.calabresi@unimi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
authors.affiliation: Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gomaraschi
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D008075:Lipoproteins, HDL; D013925:Thromboplastin
keywords: endothelium; high-density lipoprotein; monocytes; protein kinases; scavenger receptors; tissue factor