Angiotensin-(1–7) reduces cardiac effects of thyroid hormone by GSK3Β/NFATc3 signaling pathway

Abstract

Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the renin–angiotensin system (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1–7) (Ang-(1–7)) has previously been shown to counterbalance pathological effects of angiotensin II (Ang II). The aim of the present study was to investigate the effects of elevated circulating Ang-(1–7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpresses an Ang-(1–7)-producing fusion protein [TGR(A1-7)3292]. TG and wild-type (WT) rats received daily injections (i.p.) of triiodothyronine (T3; 7 µg/100 g of body weight (BW)) or vehicle for 14 days. In contrast with WT rats, the TG rats did not develop cardiac hypertrophy after T3 treatment. Indeed, TG rats displayed reduced systolic blood pressure (SBP) and cardiac hyperdynamic condition induced by hyperthyroidism. Moreover, increased plasma levels of Ang II observed in hyperthyroid WT rats were prevented in TG rats. TG rats were protected from glycogen synthase kinase 3β (GSK3β) inactivation and nuclear factor of activated T cells (NFAT) nuclear accumulation induced by T3. In vitro studies evidenced that Ang-(1–7) prevented cardiomyocyte hypertrophy and GSK3β inactivation induced by T3. Taken together, these data reveal an important cardioprotective action of Ang-(1–7) in experimental model of hyperthyroidism.