Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1, thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells.
OBJECTIVE
Plasminogen activator inhibitor-1 (PAI-1), thrombospondin-1 (THBS1) and thrombomodulin (TM) are involved in atherothrombosis. Vitamin D receptor agonists (VDRAs) provide survival/cardiovascular benefits for chronic kidney disease patients.


METHODS
The effects of VDRAs on regulating PAI-1, THBS1 and TM in human aortic smooth muscle cells (SMC) and endothelial cells (EC) were studied.


RESULTS
In SMC, paricalcitol and calcitriol downregulated the expression of PAI-1 mRNA and protein in a dose-dependent manner (EC(50) = 0.7 and 4.4 nM, respectively). Both drugs also downregulated THBS1 mRNA and protein (EC(50) = 1.6 and 3.9 nM, respectively). In contrast, paricalcitol and calcitriol upregulated TM mRNA and protein (EC(50) = 28.9 and 25.5 nM, respectively). EC did not express VDR, and VDRAs failed to induce CYP24A1, a VDR target gene. The effect of paricalcitol on THBS1 in SMC was blocked by cycloheximide, while its effect on TM and CYP24A1 was not affected, suggesting that the regulation of THBS1 by VDR may be mediated through intermediate factors, but that TM is likely a direct target of VDR.


CONCLUSIONS
VDR may play a role in atherothrombosis via regulation of PAI-1, THBS1 and TM.
Wu-Wong
J Ruth
JR
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. ruth.r.wuwong@abbott.com
Nakane
Masaki
M
Ma
Junli
J
D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004872:Ergocalciferols / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D018180:Thrombomodulin / Q000096:biosynthesis*; D019700:Thrombospondin 1 / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase
D004872:Ergocalciferols; D017395:Plasminogen Activator Inhibitor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C051321:SERPINE1 protein, human; D018180:Thrombomodulin; D019700:Thrombospondin 1; D014807:Vitamin D; C084656:paricalcitol; D003513:Cycloheximide; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol