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(Circulation. 2005;111:1666-1671.)
© 2005 American Heart Association, Inc.

Vascular Medicine

25-Hydroxyvitamin D₃-1-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds

Dalia Somjen, PhD; Yosef Weisman, MD; Fortune Kohen, PhD; Batya Gayer, MSc; Rona Limor, PhD; Orly Sharon, BSc; Niva Jaccard, MSc; Esther Knoll; Naftali Stern, MD

From the Institute of Endocrinology, Metabolism and Hypertension (D.S., R.L., O.S., E.K., N.S.) and the Metabolic Bone Disease Unit (Y.W., N.J.), Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, and Department of Biological Regulation (F.K., B.G.), Weizmann Institute of Science, Rehovot, Israel.

Reprint requests to N. Stern, MD, Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv, 64239, Israel. E-mail stern{at}tasmc.health.gov.il

Received September 27, 2004; revision received January 5, 2005; accepted January 19, 2005.

Background— 1,25(OH)₂ vitamin D₃ exerts multiple effects in human vascular smooth muscle cells (VSMCs). We therefore tested the possibility that VSMCs possess an endogenous 25-hydroxyvitamin D₃-1-hydroxylase system, the final enzyme in the biosynthetic pathway of 1,25(OH)₂D₃.

Methods and Results— We assessed the expression and activity of 25-hydroxyvitamin D₃-1-hydroxylase by real-time polymerase chain reaction and the conversion of 25(OH)D₃ into 1,25(OH)₂D₃. First, 25-hydroxyvitamin D₃-1-hydroxylase mRNA was identified in cultured VSMCs by real-time polymerase chain reaction. Second, in cells treated daily (3 days) with parathyroid hormone (66 nmol/L), estradiol-17ß (30 nmol/L), raloxifene (3 µmol/L), and the phytoestrogens genistein (3 µmol/L), biochainin A (3 µmol/L), and 6-carboxy biochainin A (30 nmol/L), 25-hydroxyvitamin D₃-1-hydroxylase mRNA increased by 43±13%, (P<0.05) 7±24% (P=NS), 176±28% (P<0.01), 65±11% (P<0.05), 152±24% (P<0.01), and 71±9% (P<0.05), respectively. Third, production of 1,25(OH)₂D₃ from 25(OH)D₃ was seen with a Km of 25 ng/mL and increased dose dependently after treatment with parathyroid hormone, genistein, and the phytosetrogen derivative 6-carboxy biochainin A. Estradiol-17ß and biochainin A also increased the generation of 1,25(OH)₂D₃ by 40±23% (P<0.05) and 55±13% (P<0.05), respectively.

Conclusions— We provide here the first evidence for the expression of an enzymatically active 25(OH)D₃-1-hydroxylase system in human VSMCs, which can be upregulated by parathyroid hormone and estrogenic compounds. Because exogenous vitamin D inhibits VSMC proliferation, the role of this system as an autocrine mechanism to curb changes in VSMC proliferation and phenotype is a subject for future investigation.

Key Words: molecular biology • vitamin D • vasculature • muscle, smooth • parathyroid hormone

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