| Somjen D, Weisman Y, Kohen F, Gayer B, Limor R, Sharon O, Jaccard
N, Knoll E, Stern N. |
| Institute of Endocrinology, Metabolism and Hypertension and the Metabolic
Bone Disease Unit, Tel Aviv Sourasky Medical Centre and Sackler Faculty
of Medicine, Tel Aviv University, Tel Aviv, and Department of Biological
Regulation, Weizmann Institute of Science, Rehovot, Israel. |
BACKGROUND: 1,25(OH)2 VITAMIN
D 3 exerts multiple effects in human vascular smooth muscle
cells (VSMCs). We therefore tested the possibility that VSMCs possess
an endogenous 25-hydroxyVITAMIN
D 3-1alpha-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
D 3-1alpha-hydroxylase by real-time polymerase chain reaction
and the conversion of 25(OH)D3 into 1,25(OH)2D3. First, 25-hydroxyVITAMIN
D 3-1alpha-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-17beta
(30 nmol/L), RALOXIFENE (3
micromol/L), and the phytoestrogens genistein (3 micromol/L), biochainin
A (3 micromol/L), and 6-carboxy biochainin A (30 nmol/L), 25-hydroxyVITAMIN
D 3-1alpha-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-17beta
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)D3-1alpha-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.
|
