title: Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cells is mediated by endoglin.
abstract: Endoglin, a transforming growth factor β (TGF-β) receptor type III, is co-expressed with endothelial nitric oxide synthase (eNOS) in aortic endothelium in atherosclerotic plaques of mice. Interestingly, atorvastatin (ATV) is able to increase both endoglin and eNOS expression and reduce plaque size beyond its lipid lowering effects but by unknown mechanisms. We hypothesized whether inflammation modulates ATV-dependent induction of endoglin and eNOS expression in vitro in endothelial cells and whether ATV-induced eNOS expression is regulated via endoglin. After treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α, endoglin and eNOS protein expression was reduced, concomitantly with increased levels of cell surface VCAM-1 and soluble endoglin, as determined by flow cytometry, Western blot and ELISA analyses. By contrast, ATV treatment increased endoglin and eNOS protein expression, while preventing TNF-α-mediated downregulation of endoglin and eNOS protein levels. Moreover, suppression of endoglin using small interfering RNA (siRNA), but not inhibition of TGF-β signaling with SB431542, abrogated ATV-induced eNOS expression. These results suggest that ATV treatment prevents inflammation-reduced endoglin and eNOS expression in endothelial cells and that ATV-induced eNOS expression strongly depends on the proper expression of endoglin in HUVECs. Possible implications of these findings might be reflected in pathological conditions characterized by reduced expression of endoglin and eNOS as for example in hereditary hemorrhagic telangiectasia or in other endothelial dysfunctions.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Zemankova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Varejckova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: E
authors.initials: E
authors.lastname: Dolezalova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Fikrova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Jezkova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Rathouska
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Hradec Kralove, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Cerveny
authors.affiliation: Center for Biological Research, Spanish National Research Council (CSIC), and Biomedical Research Networking Center on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Botella
authors.affiliation: Center for Biological Research, Spanish National Research Council (CSIC), and Biomedical Research Networking Center on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Bernabeu
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Nemeckova
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Biological and Medical Sciences, Hradec Kralove, Czech Republic. petr.nachtigal@faf.cuni.cz.
authors.forename: P
authors.initials: P
authors.lastname: Nachtigal
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000069059:Atorvastatin / Q000494:pharmacology*; D002478:Cells, Cultured; D000071063:Endoglin; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III