Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells

Low blood concentrations of 25-hydroxyvitamin D3 are associated with increased mortality, while some studies suggest improved cardiovascular outcomes with vitamin D3 supplementation in chronic kidney disease. However, the physiological effects of vitamin D3 on the cardiovascular system remain poorly understood making it difficult to determine whether vitamin D3 supplementation might provide cardiovascular benefit or even cause harm. Thus here we investigated the effects of chronic 1,25-dihydroxyvitamin D3 treatment on intracellular signaling in human coronary artery smooth muscle cells (HCASMCs) and found that 1,25-dihydroxyvitamin D3 significantly potentiated endothelin (ET-1) signaling. Specifically, 1,25-dihydroxyvitamin D3 (24-h pretreatment) caused a more than threefold enhancement in both ET-1-induced intracellular calcium mobilization and extracellular signal-regulated kinase (ERK) activation. This 1,25-dihydroxyvitamin D3-elicited signaling enhancement was not observed for either vasopressin or carbachol. With the use of endothelin receptor (ETR) isoform-selective antagonists, ETRA was found to be primarily responsible for the 1,25-dihydroxyvitamin D3-induced ET-1 responsiveness and yet ETRA mRNA expression and protein abundance were unaltered following 1,25-dihydroxyvitamin D3 treatment. While there was an increase in ETRB mRNA expression in response to 1,25-dihydroxyvitamin D3, the protein abundance of ETRB was again unchanged. Finally, ETRA/ETRB heterodimerization was not detected in HCASMCs in either the absence or presence of 1,25-dihydroxyvitamin D3. Together, these data show for the first time that 1,25-dihydroxyvitamin D3 enhances endothelin responsiveness in HCASMCs and that the effect is mediated through ETRA.

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Gene Expression Profiling In Rat Smooth Muscle Cells Reveals Novel Regulatory Pathways Modulated by Rapamycin and Paclitaxel

The Internet Journal of Genomics and Proteomics ◽

10.5580/1501 ◽

2007 ◽

Vol 3 (1) ◽

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Muscle Cells ◽

Regulatory Pathways

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Elevated phosphorus modulates vitamin D receptor-mediated gene expression in human vascular smooth muscle cells

AJP Renal Physiology ◽

10.1152/ajprenal.00492.2006 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1592-F1604 ◽

Cited By ~ 16

Author(s):

J. Ruth Wu-Wong ◽

Masaki Nakane ◽

Junli Ma ◽

Xiaoan Ruan ◽

Paul E. Kroeger

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Vitamin D Receptor ◽

Target Genes ◽

Muscle Cells ◽

T Antigen ◽

Mechanism Analysis ◽

Human Coronary Artery

Clinical observations show that an increase in serum inorganic phosphorus (Pi) is linked to higher cardiovascular (CV) mortality, while vitamin D receptor (VDR) agonist therapy is associated with survival benefit in stage 5 chronic kidney disease. Smooth muscle cells (SMCs) play an important role in CV pathophysiology, but the interaction between Pi and the VDR signaling pathway in SMCs is not known. Real-time RT-PCR studies revealed that elevated Pi (2.06 mM) modulated VDR-mediated regulation of a panel of genes including thrombomodulin and osteopontin in SMCs. DNA microarray results demonstrated that increasing Pi from 0.9 to 2.06 mM exerted a widespread modulating effect on VDR-mediated gene expression. A total of 325 target genes were affected by paricalcitol at 0.9 mM Pi, with 195 up- and 130 downregulated. The number of target genes affected by paricalcitol at 2.06 mM Pi decreased to 86, with 55 up- and 31 downregulated. VDR-mediated gene expression in As4.1 cells (a juxtaglomerular cell-like cell line derived from kidney tumors in SV40 T-antigen transgenic mice) and peroxisome proliferator-activated receptor (PPAR)γ-mediated gene expression in SMCs were also altered by elevated Pi, suggesting that the observation is not unique to VDR in SMCs. Mechanism analysis showed that elevated Pi had no significant effect on VDR or PPARγ protein level but altered the cytosolic vs. nuclear distribution of NF-κB or nuclear receptor corepressor 1 (NCoR1). Our results demonstrate for the first time that elevated Pi affects VDR-mediated gene expression in human coronary artery SMCs and the effect is not limited to VDR in SMCs.

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