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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 9; pp. 2049 - 2055
• Main Authors: Fukuyama, Kae, Ichiki, Toshihiro, Imayama, Ikuyo, Ohtsubo, Hideki, Ono, Hiroki, Hashiguchi, Yasuko, Takeshita, Akira, Sunagawa, Kenji
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2006; Hagerstown, MD Lippincott
• Subjects: Angiotensin II - pharmacology; Animals; Aorta, Thoracic - cytology; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Catheterization; Cells, Cultured; Cyclic AMP - genetics; Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors; Cyclic AMP Response Element-Binding Protein - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Activation - drug effects; Fundamental and applied biological sciences. Psychology; General and cellular metabolism. Vitamins; General aspects; Hyperthyroidism - physiopathology; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Medical sciences; Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation - drug effects; Proteins - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone - metabolism; Response Elements - physiology; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Triiodothyronine - pharmacology; Tunica Intima - physiopathology; Vertebrates: cardiovascular system; Vascular disease; Vascular remodeling; Binding protein; Octapeptide; Renin angiotensin system; Peptide hormone; Atherosclerosis; Cardiovascular disease; Thyroid hormone; Angiotensin II; cAMP response element binding protein
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000233358.87583.01

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.