title: Direct effect of F12511, a systemic inhibitor of Acyl-CoA cholesterol acyltransferase on bovine aortic endothelial cells.
abstract: F12511(S)-2',3',5'-trimethyl-4'-hydroxy-alpha-dodecylthio-alpha-phenylacetanilide (F12511) is a new Acyl-CoA cholesterol acyltransferase (ACAT) inhibitor that not only reduces the plasma cholesterol levels but also has anti-atherosclerotic actions in animals models. The study's aim was to analyze if F12511 may directly modify the ability of tumor necrosis factor--alpha (TNF-alpha)-incubated bovine aortic endothelial cells (BAEC) to express endothelial nitric oxide synthase (eNOS) protein and inflammatory-related proteins such as platelet endothelial cell adhesion molecule (PECAM) and CD40 ligand (CD40L). The addition of increasing concentrations of F12511 (10 to 10 mol/L) failed to modify the level of eNOS protein expressed in control BAEC. TNF-alpha (10 ng/mL) reduced the expression of eNOS protein. In TNF-alpha--incubated BAEC, F12511 protected eNOS expression in a concentration-dependent manner. TNF-alpha stimulated the expression of both CD40L and PECAM in cultured BAEC. F12511 (10 mol/L) failed to modify the expression of CD40L and PECAM in control and TNF-alpha-incubated BAEC. Reverse transcriptase polymerase chain reaction showed a marked expression of the ACAT-2 isoform and absent of expression of the ACAT-1 isoform in BAEC. The presence of ACAT-2 isoform in BAEC was further confirmed by Western blot. F12511 failed to modify the expression of the proinflammatory associated proteins PECAM and CD40L in the endothelium but protected eNOS expression in the endothelial cells exposed to inflammatory conditions.
authors.affiliation: Cardiovascular Research Unit, Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: José J
authors.initials: JJ
authors.lastname: Zamorano-León
authors.forename: Ruth
authors.initials: R
authors.lastname: Fernández-Sánchez
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: López Farré
authors.forename: Lucía
authors.initials: L
authors.lastname: Lapuente-Tiana
authors.forename: Sergio
authors.initials: S
authors.lastname: Alonso-Orgaz
authors.forename: Daniel
authors.initials: D
authors.lastname: Sacristán
authors.forename: Didier
authors.initials: D
authors.lastname: Junquera
authors.forename: André
authors.initials: A
authors.lastname: Delhon
authors.forename: Antonio
authors.initials: A
authors.lastname: Conesa
authors.forename: Petra J
authors.initials: PJ
authors.lastname: Mateos-Cáceres
authors.forename: Carlos
authors.initials: C
authors.lastname: Macaya
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000813:Anilides; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology*; D023201:CD40 Ligand / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D000813:Anilides; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; C418062:eflucimibe; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D002785:Sterol O-Acyltransferase