Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells.
Expression of functionally active thrombomodulin (TM) on endothelial cells is critical for vascular thromboresistance. 3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can protect the vasculature from inflammation and atherosclerosis caused by cholesterol-dependent and cholesterol-independent mechanisms. In the present study, the effects of atorvastatin on TM expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells (HAECs) were investigated. When rabbits were fed a 0.5% cholesterol diet with and without supplementation with atorvastatin for 9 weeks, the neointimal area in the thoracic aorta of the atorvastatin-treated group was significantly reduced and there was significant induction of TM protein expression. In HAECs, TNFalpha treatment decreased the expression of TM in a time- and dose-dependent manner and atorvastatin pretreatment upregulated the expression of TM mRNA and protein in HAECs with or without TNFalpha treatment. Atorvastatin also inhibited monocyte adhesion to control and TNFalpha-treated HAECs via TM expression. ERK1/2 phosphorylation was significantly reduced by 24 h pretreatment with atorvastatin, whereas TNFalpha increased the phosphorylation of the MAPKs, p38, JNK, and ERK1/2. Blocking the transcriptional activation of NF-kappaB and nuclear translocation of NF-kappaB p65 prevented the TNFalpha-induced downregulation of TM. Atorvastatin regulated TM expression in control and TNFalpha-treated HAECs by inhibiting the activation of ERK and NF-kappaB. The increase in endothelial TM activity in response to atorvastatin constitutes an important pleiotropic effect of this commonly used compound and may be of clinical significance in cardiovascular disorders in which deficient endothelial TM plays a pathophysiological role.
Lin
Shing-Jong
SJ
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Hsieh
Fang-Yu
FY
Chen
Yung-Hsiang
YH
Lin
Chia-Chi
CC
Kuan
I-I
II
Wang
Shu-Huei
SH
Wu
Chau-Chung
CC
Chien
Hsiung-Fei
HF
Lin
Fen-Yen
FY
Chen
Yuh-Lien
YL
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000069059:Atorvastatin; D016022:Case-Control Studies; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D011897:Random Allocation; D018180:Thrombomodulin / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
D002791:Cholesterol, Dietary; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin