VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells.
Vitamin D analogs such as paricalcitol and calcitriol that activate the vitamin D receptor (VDR) provide survival benefit for Stage 5 chronic kidney disease (CKD) patients, possibly associated with a decrease in cardiovascular (CV)-related incidents. Phenotypic changes of smooth muscle cells play an important role in CV disease. The role of vitamin D analogs in modulating gene expression in smooth muscle cells is still not well understood. In this study, DNA microarray analysis of approximately 22,000 different human genes was used to characterize the VDR-mediated gene expression profile in human coronary artery smooth muscle cells (CASMC) at rest. Cells in serum free medium were treated with 0.1 microM calcitriol (1alpha,25-dihydroxyvitamin D(3)) or paricalcitol (19-nor-1alpha,25-(OH)(2)D(2)) for 30 h. A total of 181 target genes were identified, with 103 genes upregulated and 78 downregulated (>two fold changes in either drug treatment group with P < 0.01). No significant difference was observed between calcitriol and paricalcitol. Target genes fell into various categories with the top five in cellular process, cell communication, signal transduction, development, and morphogenesis. Twenty-two selected genes linked to the CV system were also impacted. Real-time RT-PCR and/or Western blotting analysis were employed to confirm the expression patterns of selected genes such as 25-hydroxyvitamin D-24-hydroxylase, Wilms' tumor gene 1, transforming growth factorbeta3, plasminogen activator inhibitor-1, thrombospondin-1 (THBS1), and thrombomodulin (TM). This study provides insight into understanding the role of VDR in regulating gene expression in resting smooth muscle cells.
Wu-Wong
J Ruth
JR
Department of Integrative Pharmacology, Abbott Laboratories, Abbott Park, Illinois 60064, USA. ruth.r.wuwong@abbott.com
Nakane
Masaki
M
Ma
Junli
J
Ruan
Xiaoan
X
Kroeger
Paul E
PE
D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016000:Cluster Analysis; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004872:Ergocalciferols / Q000494:pharmacology; D020869:Gene Expression Profiling; 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*; D020411:Oligonucleotide Array Sequence Analysis; D018167:Receptors, Calcitriol / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014815:Vitamins / Q000494:pharmacology
D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; D014815:Vitamins; C084656:paricalcitol; D002117:Calcitriol