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Vitamin D receptor activators modulate the expression of thrombomodulin, thrombospondin and plasminogen activator inhibitor‐1 in human coronary artery smooth muscle cells
Author(s) -
WuWong J. Ruth,
Nakane Masaki,
Ma Junli
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1111-b
Subject(s) - paricalcitol , calcitriol , calcitriol receptor , endocrinology , medicine , plasminogen activator , osteopontin , thrombomodulin , plasminogen activator inhibitor 1 , vitamin d and neurology , thrombin , parathyroid hormone , secondary hyperparathyroidism , calcium , platelet
Vitamin D receptor activators (VDRAs, 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 cardiovascular (CV) function. Increases in the expression of thrombospondin‐1 (THBS1, an extracellular matrix glycoprotein that affects vascular function) and plasminogen activator inhibitor‐1 (PAI‐1) have been linked to atherosclerosis and risks of CV morbidity and mortality. Thrombomodulin (TM), an anticoagulant glycoprotein, functions to modulate thrombin activity. Materials and Methods Primary culture of human coronary artery smooth muscle cells were treated with paricalcitol or calcitriol to assess their effects on PAI‐1, TM and THBS1 expression. Results Paricalcitol and calcitriol down‐regulated the expression of PAI‐1 mRNA and protein in a dose‐dependent manner. (EC 50 = 3.0 and 2.8 nM for paricalcitol and calcitriol, respectively). Both compounds also down‐regulated the expression of THBS1 mRNA in a dose‐dependent manner. In contrast, paricalcitol and calcitriol up‐regulated the expression of TM mRNA and protein in a dose‐dependent manner (EC 50 = 3.5 and 1.5 nM for paricalcitol and calcitriol, respectively). The effect of paricalcitol on suppressing PAI‐1 and THBS1 was blocked by cycloheximide, suggesting that protein synthesis was required. The effect of paricalcitol on up‐regulating TM is independent of cycloheximide treatment. Conclusion These results demonstrate that VDRAs modulate the expression of factors associated with thrombogenicity and vascular injury, which may be an important factor contributing to the survival benefits of VDRAs observed in CKD patients.