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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2049.)
© 2006 American Heart Association, Inc.

Vascular Biology

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

Kae Fukuyama; Toshihiro Ichiki; Ikuyo Imayama; Hideki Ohtsubo; Hiroki Ono; Yasuko Hashiguchi; Akira Takeshita; Kenji Sunagawa

From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Correspondence to Toshihiro Ichiki, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp

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— 3,3',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 µg/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.

The molecular mechanism of anti-atherosclerotic effects of thyroid hormone is poorly defined. We showed in the present study that thyroid hormone inhibits cAMP response element binding protein activity and suppresses angiotensin II-induced cytokine expression and hypertrophy of vascular smooth muscle cells, which may be involved in anti-atherosclerotic effect.

Key Words: angiotensin II • cAMP response element binding protein • thyroid hormone • vascular remodeling

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