Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification.
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-alpha 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.
Sato
Yoji
Y
Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8501, Japan. yoji@nihs.go.jp
Nakamura
Ryo
R
Satoh
Mitsutoshi
M
Fujishita
Kayoko
K
Mori
Satoko
S
Ishida
Seiichi
S
Yamaguchi
Teruhide
T
Inoue
Kazuhide
K
Nagao
Taku
T
Ohno
Yasuo
Y
D000818:Animals; D001011:Aorta / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002114:Calcinosis / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics; D007037:Hypothyroidism / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D053495:Osteopontin; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics; D037021:Thyroid Hormone Receptors alpha / Q000502:physiology; D013963:Thyroid Hormones / Q000097:blood / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology; D014652:Vascular Diseases / Q000517:prevention & control*; D000097568:Matrix Gla Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002118:Calcium; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D053495:Osteopontin; D012795:Sialoglycoproteins; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D014284:Triiodothyronine; D000097568:Matrix Gla Protein; C525809:BMP4 protein, human; C525811:Bmp4 protein, rat; C506895:SPP1 protein, human; C506897:Spp1 protein, rat; C051795:teleocalcin