title: Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells.
abstract: Berberine (BBR) is a novel natural hypolipidemic agent. This study investigates whether BBR, similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. BBR enhanced tumor necrosis factor-alpha (TNF-alpha) and thrombin induced TF expression in human endothelial cells by 3.5-fold. These effects were paralleled by an enhanced TF surface activity. In contrast, expression of TF pathway inhibitor was impaired. BBR enhanced TNF-alpha induced TF mRNA expression; however, TF promoter activity was inhibited. Activation of ERK and p38 remained unaffected, while c-Jun terminal NH(2) kinase was inhibited. BBR reduced TF mRNA degradation rates, prolonging its half-life from 1.1 to 4.3 h. The HMG-CoA reductase inhibitor simvastatin impaired thrombin induced TF expression, and BBR blunted this inhibition. Simvastatin did not affect TNF-alpha induced TF expression, and BBR enhanced TF under these conditions. Administration of BBR (100 mg/kg/d) increased TF activity and impaired TFPI expression in carotid artery of ApoE(-/-) mice. BBR enhances TF via mRNA stabilization at clinically relevant concentrations. Clinical application of BBR, either as an alternative to or in combination with statins, should be considered with caution.
authors.affiliation: Cardiovascular Research, Physiology Institute, University of Zürich, Switzerland.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Holy
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology*; D001599:Berberine / Q000494:pharmacology*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D008074:Lipoproteins; D014409:Tumor Necrosis Factor-alpha; C051928:lipoprotein-associated coagulation inhibitor; D001599:Berberine; D013925:Thromboplastin; D019821:Simvastatin; D048031:JNK Mitogen-Activated Protein Kinases