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Abstract-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 3Ј,3,5-triiodo-L-thyronine (T 3 ) on the expression of calcificationassociated genes in rat aortic smooth muscle cells (RAOSMCs). Quantitative RT-PCRs revealed that a physiological concentration of T 3 (15 pmol/L free T 3 ) 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, T 3 significantly stimulated luciferase activity. In addition, RNA interference against thyroid hormone receptor-␣ gene diminished the effect of T 3 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 T 3 /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. (Circ Res. 2005;97:550-557.)Key Words: calcium Ⅲ gene expression Ⅲ nuclear receptors Ⅲ vascular smooth muscle Ⅲ thyroid hormone T hyroid hormone has marked effects on differentiation, development, and metabolic balance of virtually every body tissue. The action of thyroid hormone is mediated by highaffinity thyroid hormone nuclear receptors (TRs), which recognize specific response elements in the promoters of target genes and regulate their transcriptional activity in response to the hormone. Alterations in thyroid hormone levels have a profound impact on the cardiovascular system, which include changes in myocardial contractility, heart rate, and resistance of peripheral vasculature. Hyperthyroidism leads to positive inotropic, lusitropic, and chronotropic effects on the heart and low systemic vascular resistance, whereas the opposite is observed in hypothyroidism. In myocardium, the mechanisms for these changes are based on altered expression levels of several key proteins involved in the regulation of intracellular ion homeostasis. The effects of thyroid hormone on cardiac contractility as well as rates of contraction and relaxation are mainly mediated by increases in the levels of the sarcoplasmic reticulum Ca 2ϩ -ATPase and decreases in its inhibitor phospholamban in cardiomyocytes. 1 The positive chronotropic effect of th...

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