Thyroid Hormone Inhibits Vascular Remodeling Through Suppression of cAMP Response Element Binding Protein Activity

Abstract

Objective-Although accumulating evidences suggest that impaired thyroid function is a risk for ischemic heart disease, the molecular mechanism of anti-atherosclerotic effects of thyroid hormone is poorly defined. We examined whether thyroid hormone affects signaling pathway of angiotensin II (Ang II), which is critically involved in a broad aspect of cardiovascular disease process. Methods and Results-3,3Ј,5-triiodo-L-thyronine (T3) did not show a significant effect on Ang II-induced activation of extracellular signal-regulated protein kinase or p38 mitogen-activated protein kinase in vascular smooth muscle cells (VSMCs), whereas T3 inhibited Ang II-induced activation of cAMP response element (CRE) binding protein (CREB), a nuclear transcription factor involved in the vascular remodeling process. Coimmunoprecipitaion assay revealed the protein-protein interaction between thyroid hormone receptor and CREB. T3 reduced an expression level of interleukin (IL)-6 mRNA, CRE-dependent promoter activity, and protein synthesis induced by Ang II. Administration of T3 (100 g/100 g for 14 days) to rats attenuated neointimal formation after balloon injury of carotid artery with reduced CREB activation and BrdU incorporation. Conclusion-These results suggested that T3 inhibits CREB/CRE signaling pathway and suppresses cytokine expression and VSMCs proliferation, which may account for, at least in part, an anti-atherosclerotic effect of thyroid hormone.

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

“…The lack of TRE sites on genes associated with NE differentiation and cell invasion can explain the null effect of T3 on the basal expression of these genes, suggesting that T3 acts indirectly in the ISO response. Studies have demonstrated a protein-protein interaction between nuclear thyroid hormone receptors and CREB in the presence of T3 (a T3-TR-CREB complex), reducing the ability of PKA to phosphorylate CREB (29,70). In our study, T3 did not fully prevent the phosphorylation of CREB, suggesting that the antagonistic effect of T3 on the β-adrenergic pathway does not necessarily occur primordially at this level.…”

“…As mentioned before, this unresponsiveness could be related to the dedifferentiated state and/or the invasive capacity of these cells. TRβ1, the nuclear thyroid receptor, has been identified in both LNCaP and DU145 cells (29); however, T3 exerts proliferative effects only in LNCaP cells (27,62). Overall, our data in vitro and in vivo indicate that T3 restrains cancer progression mediated by β-adrenergic receptors in a model of differentiated cancer.…”

“…In the combined group, T3 impeded the increases of tumor proteins SYP and VEGF; and in vitro, T3 prevented VEGF secretion, neurite-like outgrowth and invasive capacity. It is well established that T3 acts synergistically with β-adrenergic pathways to upregulate genes that contain both CRE and TRE sites (68,69), but there is also evidence that T3 represses the expression of genes that have only CRE sites (29,70,71). The lack of TRE sites on genes associated with NE differentiation and cell invasion can explain the null effect of T3 on the basal expression of these genes, suggesting that T3 acts indirectly in the ISO response.…”

Baseline Levels and Trimestral Variation of Triiodothyronine and Thyroxine and Their Association with Mortality in Maintenance Hemodialysis Patients

“…Although adjustment for s-albumin (one of the main transporters of T3 in plasma) did not modify the observed associations, we should acknowledge that fT3 is not tantamount to T3. Several studies have, nevertheless, suggested anti-atherosclerotic effects of fT3 on the vascular bed via its effect on mitochondrial oxidative systems, induction of vasodilatory molecules, inhibition of angiotensin II receptor expression and inhibition of downstream signal transduction, mechanisms all of which do not necessarily involve the inflammatory cascade (26)(27)(28).…”

Free Triiodothyronine Concentrations are Inversely Associated with Elevated Carotid Intima-Media Thickness in Middle-Aged and Elderly Chinese Population

“…This study was supported by the grants from the Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health (1994DP131044), the China National Clinical Research Center for Metabolic Diseases diate cardiovascular outcome variables and systemic hemodynamic factors may also be involved in the relationship between thyroid hormone status and C-IMT. Nevertheless, the exact mechanisms for these associations remain unclear.. Variations in the thyroid hormone status could affect lipoprotein quality and oxidation 25) , vascular remodeling via an effect on local angiotensin signaling 26) , and endothelial function 27) . In experimental models, T3 has important effects on the vascular system, by inducing relaxation of vascular smooth muscle cells through a direct or indirect effect via activation of nitric oxide synthase and inducing adrenomedullin expression in endothelial cells 28) .…”