Published Online
on February 17, 2003

A more recent version of this article appeared on March 1, 2003

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Submitted on June 21, 2002
Revised on August 8, 2002

Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone

Kae Fukuyama; Toshihiro Ichiki^*; Kotaro Takeda; Tomotake Tokunou; Naoko Iino; Satoko Masuda; Minako Ishibashi; Kensuke Egashira; Hiroaki Shimokawa; Katsuya Hirano; Hideo Kanaide; and Akira Takeshita

From the Departments of Cardiovascular Medicine (K.F., T.I., K.T., T.T., N.I., S.M., M.I., K.E., H.S., A.T.) and Molecular Cardiology (K.H., H.K.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

^* To whom correspondence should be addressed. E-mail: ichiki{at}cardiol.med.kyushu-u.ac.jp.

Abstract--Thyroid hormone has a broad effect on cardiovascular system. 3,3',5-triiodo-L-thyronine (T3), a biologically active form of thyroid hormone, increases cardiac contractility. T3 causes arterial relaxation and reduction of systemic vascular resistance, resulting in an increase in cardiac output. However, the molecular mechanisms of vascular relaxation by T3 are incompletely characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT₁R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT₁R mRNA, with a peak at 6 hours of stimulation. Binding assay using [¹²⁵I]Sar¹-Ile⁸-Ang II revealed that AT₁R number was decreased by stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT₁R promoter activity measured by luciferase assay was reduced by 50% after 9 hours of T3 administration. mRNA stability was also decreased by T3. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis revealed that AT₁R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT₁R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT₁R gene expression may play an important role for T3-induced vascular relaxation.

Key words: hormones • receptors, angiotensin II • gene expression • mRNA stability • vascular relaxation

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