Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone

Abstract

Abstract-Thyroid hormone has a broad effect on cardiovascular system. 3,3Ј,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 (AT 1 R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT 1 R mRNA, with a peak at 6 hours of stimulation. Binding assay using [ 125 I]Sar 1 -Ile 8 -Ang II revealed that AT 1 R 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%. AT 1 R 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 transcriptionpolymerase chain reaction and Western blot analysis revealed that AT 1 R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT 1 R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT 1 R gene expression may play an important role for T3-induced vascular relaxation. T hyroid hormone has various effects on the cardiovascular system. L-Thyroxine (T4), the major secretory product of the thyroid gland is inactive. Thyroxine 5Ј-deiodinase converts T4 to an active hormone, 3,3Ј,5-triiodo-L-thyronine (T3). 1 T3 binds to thyroid hormone receptor that belongs to the nuclear receptor family. The activated thyroid hormone receptor induces gene expression through binding to thyroid hormone response element (TRE) in the promoter region of target genes. 2 An increase in left ventricular contractility, tachycardia, and reduction of systemic vascular resistance induce high cardiac output state in hyperthyroidism. The positive inotropic and chronotropic action of T3 are direct effects of T3 on cardiac myocytes, and T3 activates many gene expressions such as myosin heavy chain and calcium transport/regulatory proteins in myocytes. [3][4][5] Reduction of systemic vascular resistance is also a direct effect of T3 on vascular smooth muscle cells (VSMCs). 6 -8 A recent report showed that T3 caused rapid relaxation of VSMCs, suggesting the presence of rapid nongenomic effect of T3. 9 It was also shown that T3-induced relaxation of VSMCs was not mediated by cAMP or NO. The target genes for T3 action in VSMCs, which are involved in vascular relaxation, have not been determined.Two isoforms for angiotensin (Ang) II receptor designated type 1 receptor (AT 1 R) 10 and type 2 receptor (AT 2 R) 11 are present. AT 1 R is a G protein-coupled receptor expressed in various tissues, including blood vessel, kidney, adrenal gland, liver, and reproduc...

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).…”

MECHANISMS IN ENDOCRINOLOGY: Heart failure and thyroid dysfunction

“…Furthermore, thyroid hormone regulates the transcription of pacemaker-related genes and hyperpolarization-activated cyclic nucleotidegated channels 3 and 4 and guanine nucleotide regulatory proteins (24). In addition, T 3 modulates the expression of angiotensin receptors in vascular smooth muscle cells (25). Other cardiac genes are negatively regulated by T 3 , i.e.…”

The renin–angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations

“…Vascular RAS may participate, at least in part, in the vascular effects of thyroid hormones. Fukuyama et al (2003) demonstrated that T 3 downregulates AT 1 receptor mRNA expression at both transcriptional and post-transcriptional levels in cultured VSMCs and rat aorta. The binding assay showed a decrease in AT 1 receptor density with no alteration of the affinity to AII.…”

“…A decrease in AT 1 receptors was also observed after T 3 administration to cultures of VSMCs and rat aorta and may result from a downregulation of the AT 1 receptor due to the local generation of higher AII values. The mechanism by which thyroid hormones modulate AT 1 receptor operates at transcriptional and post-transcriptional levels (Fukuyama et al 2003).…”