Molecular pharmacological approach to elucidate direct actions of thyroid hormone on arterial blood vessels

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We recently found that thyroid hormone (TH) has a protective effect against vascular calcification, at least partly by up-regulating matrix Gla protein gene (Mgp) in aortic smooth muscle. As transforming growth factor-beta (TGFbeta) is associated with osteogenesis, we hypothesized that, TH also regulates the expression of TGFbeta isoforms in vascular smooth muscle cells. To test this hypothesis, rat aortic smooth muscle cells (RAOSMCs), cultured in the nominally TH-free medium, were treated with 3', 3, 5-taiiodo-L-thyronine (T3) for 48 hours. Quantitative RT-PCRs indicated that 24-30pM free T3 selectively facilitated gene expression of TGFbeta3 in RAOSMCs by 2-fold. Rat aortic smooth muscle from methimazole-induced hypothyroid rats also showed a 50% decrease in the TGFbeta3 mRNA level, compared to euthyroid rats. Using GeneChip RGrU34A and Ingenuity Pathway Analysis, we further identified Den as a gene whose expression is negatively associated with both TGFbeta signaling and thyroid status in vivo. As Den encodes decorin, which functions as a promoter of intimal calcification, our findings suggest that the anti-calcification activity of TH is attributable not solely to its effect on Mgp gene, but also to those on several calcification-associated genes.