Introduction: 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.
Materials and 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.
Conclusion: 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.