Effects of vitamin D analogs on the expression of plasminogen activator inhibitor-1 in human vascular cells.
BACKGROUND
Vitamin D analogs such as paricalcitol and calcitriol have been shown to provide survival benefit for Stage 5 chronic kidney disease (CKD) patients, possibly due to their positive impact on the cardiovascular system. Plasminogen activator inhibitor-1 (PAI-1) is one of the risk markers for coronary artery disease.


METHODS
Human coronary artery smooth muscle cells (SMC) and endothelial cells (CAEC) were treated with vitamin D analogs to assess the effects of the drugs on the expression of PAI-1 mRNA and protein.


RESULTS
In SMC, both paricalcitol and calcitriol down-regulated the expression of PAI-1 mRNA and protein in a dose-dependent manner. The EC(50) values of paricalcitol and calcitriol on suppressing PAI-1 mRNA were 3.0 and 2.8 nM, respectively. Interestingly, these two drugs had no significant effect on the expression of PAI-1 protein or mRNA in CAEC. Further analysis showed that CAEC did not express functional vitamin D receptor (VDR) and paricalcitol failed to induce the expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) mRNA, a gene known to be regulated by VDR. As a comparison, SMC expressed VDR and paricalcitol induced CYP24A1 mRNA in SMC (>150-fold at 10 nM) dose-dependently. The effect of paricalcitol on suppressing PAI-1 in SMC was blocked by cycloheximide, suggesting that protein synthesis was involved.


CONCLUSIONS
These results demonstrate that vitamin D analogs suppress PAI-1 in SMC, but not in CAEC. Suppression of PAI-1 in SMC may be one of the factors contributing to the survival benefits of vitamin D analog therapy in CKD patients.
Wu-Wong
J Ruth
JR
Abbott Laboratories, R4CM, AP52, 200 Abbott Park Rd., Abbott Park, IL 60064, Unites States. ruth.r.wuwong@abbott.com
Nakane
Masaki
M
Ma
Junli
J
D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
D004872:Ergocalciferols; D017395:Plasminogen Activator Inhibitor 1; D018167:Receptors, Calcitriol; C051321:SERPINE1 protein, human; D014807:Vitamin D; C084656:paricalcitol; D002117:Calcitriol