Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells.
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.
Holy
Erik W
EW
Cardiovascular Research, Physiology Institute, University of Zürich, Switzerland.
Akhmedov
Alexander
A
Lüscher
Thomas F
TF
Tanner
Felix C
FC
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
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