Blockage of angiotensin II type 2 receptor prevents thyroxine-mediated cardiac hypertrophy by blocking Akt activation.

Although most of effects of Angiotensin II (Ang II) related to cardiac remodelling can be attributed to type 1 Ang II receptor (AT(1)R), the type 2 receptor (AT(2)R) has been shown to be involved in the development of some cardiac hypertrophy models. In the present study, we investigated whether the thyroid hormone (TH) action leading to cardiac hypertrophy is also mediated by increased Ang II levels or by change on AT(1)R and AT(2)R expression, which could contribute to this effect. In addition, we also evaluated the possible contribution of AT(2)R in the activation of Akt and in the development of TH-induced cardiac hypertrophy. To address these questions, Wistar rats were treated with thyroxine (T(4), 0.1 mg/kg BW/day, i.p.), with or without AT(2)R blocker (PD123319), for 14 days. Cardiac hypertrophy was identified based on heart/body weight ratio and confirmed by analysis of atrial natriuretic factor mRNA expression. Cardiomyocyte cultures were used to exclude the influence of TH-related hemodynamic effects. Our results demonstrate that the cardiac Ang II levels were significantly increased (80%, P < 0.001) as well as the AT(2)R expression (50%, P < 0.05) in TH-induced cardiac hypertrophy. The critical involvement of AT(2)R to the development of this cardiac hypertrophy in vivo was evidenced after administration of AT(2) blocker, which was able to prevent in 40% (P < 0.01) the cardiac mass gain and the Akt activation induced by TH. The role of AT(2)R to the TH-induced cardiomyocyte hypertrophy was also confirmed after using PD123319 in the in vitro studies. These findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and provide new insights into the generation of future therapeutic strategies.

Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism.

This study assessed the behaviour of angiotensin II (Ang II) receptors in an experimental hypothyroidism model in male Wistar rats. Animals were subjected to thyroidectomy and resting for 14 days. The alteration of cardiac mass was evaluated by total heart weight (HW), right ventricle weight (RVW), left ventricle weight (LVW), ratio of HW, RVW and LVW to body weight (BW) and atrial natriuretic factor (ANF) expression. Cardiac and plasma Ang II levels and serum T3 and T4 were determined. The mRNA and protein levels of Ang II receptors were investigated by RT-PCR and Western blotting, respectively. Functional analyses were performed using binding assays. T3 and T4 levels and the haemodynamic parameters confirmed the hypothyroid state. HW/BW, RVW/BW and LVW/BW ratios and the ANF expression were lower than those of control animals. No change was observed in cardiac or plasma Ang II levels. Both AT1/AT2 mRNA and protein levels were increased in the heart of hypothyroid animals due to a significant increase of these receptors in the RV. Experiments performed in cardiomyocytes showed a direct effect promoted by low thyroid hormone levels upon AT1 and AT2 receptors, discarding possible influence of haemodynamic parameters. Functional assays showed that both receptors are able to bind Ang II. Herein, we have identified, for the first time, a close and direct relation of elevated Ang II receptor levels in hypothyroidism. Whether the increase in these receptors in hypothyroidism is an alternative mechanism to compensate the atrophic state of heart or whether it may represent a potential means to the progression of heart failure remains unknown.