Cardiac angiotensin receptor expression in hypothyroidism: back to fetal gene programme?

Thyroid hormone exerts an effect on the cardiovascular system: it influences vasomotion, through a relaxing effect on vessel smooth muscle cells, and trophism and function of cardiomyocytes, with a positive chronotropic and inotropic effect (Klein & Danzi, 2007). Many symptoms found in patients with primitive or secondary forms of hyper- and hypothyroidism are attributable to changes in haemodynamics due to modulation of peripheral vascular resistance and heart rate and contractility. Once it has entered the cardiomyocyte, thyroid hormone moves to the nucleus and binds to its specific receptors. The combination with other cofactors allows thyroid hormone to interact with specific sequences of DNA, turning the transcription of target genes on or off. To date, only a limited number of these genes have been identified and there are few data on their regulation by thyroid hormone.

An article recently published in The Journal of Physiology by Carneiro-Ramos et al. (2007) focuses on the effects of experimental hypothyroidism on the transcriptional modulation of subtypes of angiotensin II receptor, AT1 and AT2, key elements in the cardiovascular pathophysiology. Angiotensin II plays an important role in the control of blood pressure, but it also acts locally in the heart with non-haemodynamic effects, such as induction of cardiomyocyte growth, hypertrophy and fibrosis. The AT1 receptor accounts for most of these effects, whereas the role of AT2 has not yet been definitively established. Several circulating factors – like corticosteroids, insulin, growth factors and cytokines – are known to affect angiotensin II receptor expression, but little is known about the impact of thyroid hormone depletion.

Carneiro-Ramos et al. used male rats subjected to thyroidectomy as a model of hypothyroidism and compared the alteration in cardiac mass, atrial natriuretic factor (ANF) expression and AT1/AT2 expression to those of control animals. They observed a decreased heart weight (HW) and heart weight/body weight ratio (HW/BW) in hypothyroid rats when compared to controls, supporting previous evidence for a trophic action of thyroid hormone. Besides, a decrease in the ANF mRNA content was reported in the hypothyroid group. Finally, AT1 and AT2 gene expression was found to be markedly increased in the hypothyroid group compared to sham operated rats (314% and 194%, respectively, versus 100% in control). Similar changes were observed at the protein level for both AT1 and AT2 receptors, as demonstrated by a Western blotting analysis (23% and 37% increase in quantity versus controls). Interestingly, both morphological and gene expression alterations were more prominent in right than in left ventricle. AT1 and AT2 gene expression was significantly increased also in cardiomyocytes cultured in a thyroid hormone depleted medium for 24 h, excluding any haemodynamic influence on the observed expression levels.

The Authors provide some hypotheses on the physiological meaning of the up-regulation of angiotensin receptors at a low thyroid hormone status. First of all cardiomyocytes might increase their expression of AT1 and AT2 genes in order to compensate for the absence of the trophic action physiologically exerted by thyroid hormone: the high density of angiotensin receptor observed might, indeed, increase the cardiomyocyte sensitivity to thyroid hormone stimulation. Protein kinase C – an enzyme activated by the binding of AT1 to its ligand – has been indeed discovered to increase thyroid hormone expression in the heart. On the other hand, given the pro-fibrotic effect of angiotensin II, the increase in receptor level could be maladaptive, contributing to the development and progression of cardiac fibrosis and, eventually, to the clinical setting of heart failure.

Actually, a further hypothesis can be put forward. Angiotensin II receptor expression is developmentally regulated, with embryonic and newborn hearts having higher gene expression than adults (Everett et al. 1997). Sequential analysis of mRNA content in rat hearts showed the highest level for AT1 mRNA on the 19th day of fetal life, and the lowest 90 days after birth. With regard to AT2 mRNA, it could only be detected in the developing heart. Therefore, the increase in angiotensin II receptor gene expression documented in rat submitted to thyroidectomy could reflect a regression to the fetal gene programme, induced by low circulating level of thyroid hormone. The concentration of biologically active thyroid hormone, T3, remains low during fetal life and sharply increases immediately after birth. In the fetal heart, the unligated thyroid hormone receptor TRα behaves as an aporeceptor and represses some cardiac genes, while in the early postnatal life, the availability of T3 releases this blockade (Mai et al. 2004). This kind of transcriptional regulation has been observed for genes encoding ion channels involved in cardiac contractile activity – namely HCN2, KCNE1, KCBN1, KCNA5, KCNQ1 – and for the gene encoding the other subtype of thyroid hormone receptor, TRβ. TRα might, then, act as a molecular switch adjusting heart function in the transition from fetal to postnatal life. The deficiency of thyroid hormone induced by thyroidectomy in rats by Carneiro-Ramos et al. probably represents a stimulus to the restoration of the fetal gene programme, i.e. in the case of angiotensin II receptors, to the up-regulation of AT1 and AT2.

One observation reported in the article is hardly explained by this hypothesis: ANF mRNA was lower in hypothyroid rats if compared to control, while higher ANF expression levels have been described in fetal than in adult ventricles. On the other hand, ANF mRNA content was assessed only in tissues from excised hearts and not also from cultured cardiomyocytes. Thus, factors other than thyroid hormone circulating concentration may have influenced the expression of ANF.

Changes in gene expression toward the fetal pattern have been described – together with hypertrophy, fibrosis and ventricular remodelling – also in heart failure, which is often related to low levels of T3 (Klein & Danzi, 2007), and there is strong evidence that altered TRα gene expression is responsible for these modifications (Kinugawa et al. 2001). On the other hand, most studies have focused on a limited number of genes, so that few data are available other than the decreased expression of α-MHC and increased expression of β-MHC in failing left ventricles. Other studies are therefore required to clarify the impact of low thyroid hormone levels on gene expression of normal and failing hearts, with particular regard to those genes, like AT1 and AT2, which play a fundamental role in the cardiac responsiveness to the renin–angiotensin system. Nonetheless, given the importance of both thyroid status and renin–angiotensin system for the pathogenesis and prognosis of heart failure, this article sheds new light on the possible interaction between these two variables previously considered as independent.