Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism

Abstract

Nitric oxide mediates a wide array of cellular functions in many tissues. It is generated by three known isoforms of nitric oxide synthases (NOS). Recently, the endothelial isoform, NOSIII, was shown to be abundantly expressed in the rat thyroid gland and its expression increased in goitrous glands. In this study, we analyzed whether NOSIII is expressed in human thyroid tissue and whether levels of expression vary in different states of thyroid gland function. Semiquantitative RT-PCR was used to assess variations in NOSIII gene expression in seven patients with Graves' disease, one with a TSH-receptor germline mutation and six hypothyroid patients (Hashimoto's thyroiditis). Protein expression and subcellular localization were determined by immunohistochemistry (two normal thyroids, five multinodular goiters, ten hyperthyroid patients and two hypothyroid patients). NOSIII mRNA was detected in all samples: the levels were significantly higher in tissues from hyperthyroid patients compared with euthyroid and hypothyroid patients. NOSIII immunoreactivity was detected in vascular endothelial cells, but was also found in thyroid follicular cells. In patients with Graves' disease, the immunostaining was diffusely enhanced in all follicular cells. A more intense signal was observed in toxic adenomas and in samples obtained from a patient with severe hyperthyroidism due to an activating mutation in the TSH receptor. In multinodular goiters, large follicles displayed a weak signal whereas small proliferative follicles showed intense immunoreactivity near the apical plasma membrane. In hypothyroid patients, NOSIII immunoreactivity was barely detectable. In summary, NOSIII is expressed both in endothelial cells and thyroid follicular cells. The endothelial localization of NOSIII is consistent with a role for nitric oxide in the vascular control of the thyroid. NOSIII expression in thyroid follicular cells and the variations in its immunoreactivity suggest a possible role for nitric oxide in thyrocyte function and/or growth.

Endothelium-dependent responses in human isolated thyroid arteries from donors

“…Thyroid vascular expansion and endothelial cell proliferation in goitrous rats are significantly inhibited after treatment with the NO synthase inhibitor -NMMA (Colin et al 1997), thus suggesting a role for NO in the abnormal vascular changes in thyroid hyperplasia. It remains to be determined whether EDHF, due to its powerful relaxation effects, may represent a novel mechanism for regulating vascularity and maintaining a high tissue perfusion in the thyroid gland.…”

“…Nitric oxide synthase, the enzyme responsible for the formation of NO (Palmer et al 1988) is present in the thyroid follicular cells and in endothelial cells of the human thyroid gland (Colin et al 1997), and human thyrocites produce the endogenous NO synthase inhibitor asymmetric-dimethyl--arginine (ADMA; Millatt et al 2000). NO production, measured as plasma nitrite-plusnitrate concentrations, is decreased in hyperthyroid patients when compared with controls (Hermenegildo et al 2002).…”

The relationships between endothelial nitric oxide synthase polymorphisms and the formation of intracranial aneurysms in the Korean population

“…2 Neuronal NOS is mainly expressed in neurons of the central 31 and peripheral nervous systems, but can also be found in other cells such as skeletal muscle myocytes, 10 lung epithelial cells, 3 and skin mast cells. 36 Endothelial NOS is mainly expressed by endothelial cells and can be found in neurons, 7 dermal fibroblasts, 40 epidermal keratinocytes, 36 thyroid follicular cells, 5 hepatocytes, and smooth muscle cells. 6 Inducible NOS is expressed in many cell types, including chondrocytes, 22 epithelial cells, 3 hepatocytes, 11 glial cells, and some types of immune cells.…”

Thyrocyte release of asymmetric dimethylarginine does not account for human thyrocyte inhibition of endothelial cell cyclic GMP

“…The rat thyroid gland expresses all three NOS isoforms (5), and eNOS expression has been demonstrated in human thyrocytes (7). We have previously shown that NO donors stimulate the production of cGMP in both primary human thyrocytes and SGHTL-189 cells, indicating that the NO-cGMP signalling pathway may play a role in thyroid function (16).…”

“…Colin et al (5) reported increased expression of both eNOS and nNOS in rats after goitre induction. Moreover, increased thyroid eNOS expression was reported in hyperthyroid patients, suggesting a possible role for NO in thyroid growth (7).…”