Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity.
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.


RESULTS
3,3',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 microg/100 g for 14 days) to rats attenuated neointimal formation after balloon injury of carotid artery with reduced CREB activation and BrdU incorporation.


CONCLUSIONS
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.
Fukuyama
Kae
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
Ichiki
Toshihiro
T
Imayama
Ikuyo
I
Ohtsubo
Hideki
H
Ono
Hiroki
H
Hashiguchi
Yasuko
Y
Takeshita
Akira
A
Sunagawa
Kenji
K
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002404:Catheterization; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006980:Hyperthyroidism / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014284:Triiodothyronine / Q000494:pharmacology*; D017539:Tunica Intima / Q000503:physiopathology; D000093242:Interleukin-6 Inhibitors
D000804:Angiotensin II; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D000093242:Interleukin-6 Inhibitors