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(Circulation Research. 2005;97:550.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Thyroid Hormone Targets Matrix Gla Protein Gene Associated With Vascular Smooth Muscle Calcification

Yoji Sato, Ryo Nakamura, Mitsutoshi Satoh, Kayoko Fujishita, Satoko Mori, Seiichi Ishida, Teruhide Yamaguchi, Kazuhide Inoue, Taku Nagao, Yasuo Ohno

From the Divisions of Cellular and Gene Therapy Products (Y.S., R.N., S.M., T.Y.), Biosignaling (K.F., K.I.), and Pharmacology (S.I., Y.O.), National Institute of Health Sciences (T.N.), Tokyo, Japan; and the Department of Pharmacology and Toxicology (R.N., M.S.), Toho University, Faculty of Pharmaceutical Sciences, Chiba, Japan.

Correspondence to Yoji Sato, PhD, Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kami-yoga, Setagaya, Tokyo 158-8501, Japan. E-mail yoji{at}nihs.go.jp

Thyroid hormones have marked cardiovascular effects in vivo. However, their direct effects on vascular smooth muscle cells have been unclear. Because thyroid hormones play critical roles in bone remodeling, we hypothesized that they are also associated with vascular smooth muscle calcification, one of the pathological features of vascular sclerosis. To test this hypothesis, we examined the effects of 3',3,5-triiodo-L-thyronine (T₃) on the expression of calcification-associated genes in rat aortic smooth muscle cells (RAOSMCs). Quantitative RT-PCRs revealed that a physiological concentration of T₃ (15 pmol/L free T₃) increased mRNA level of matrix Gla protein (MGP), which acts as a potent inhibitor of vascular calcification in vivo, by 3-fold in RAOSMCs, as well as in cultured human coronary artery smooth muscle cells. In RAOSMCs transiently transfected with a luciferase reporter gene driven by the MGP promoter, T₃ significantly stimulated luciferase activity. In addition, RNA interference against thyroid hormone receptor- gene diminished the effect of T₃ on MGP expression. Aortic smooth muscle tissues from methimazole-induced hypothyroid rats (400 mg/L drinking water; 4 weeks) also showed a 68% decrease in the MGP mRNA level, as well as a 33% increase in calcium content compared with that from the control euthyroid animals, whereas hyperthyroidism (0.2 mg T₃/kg IP; 10 days) upregulated MGP mRNA by 4.5-fold and reduced calcium content by 11%. Our findings suggest that a physiological concentration of thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to prevention of vascular calcification in vivo.

Key Words: calcium • gene expression • nuclear receptors • vascular smooth muscle • thyroid hormone

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