Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Basic Res Cardiol. 2010 May;105(3):325-35. doi: 10.1007/s00395-010-0089-0. Epub 2010 Feb 14.
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.
虽然血管紧张素 II（Ang II）的大多数作用与心脏重构有关，但可以归因于 1 型 Ang II 受体（AT（1）R），2 型受体（AT（2）R）已被证明参与了一些心脏肥大模型的发展。在本研究中，我们研究了甲状腺激素（TH）导致心脏肥大的作用是否也通过增加 Ang II 水平或通过改变 AT（1）R 和 AT（2）R 表达来介导，这可能有助于这种作用。此外，我们还评估了 AT（2）R 在 Akt 激活和 TH 诱导的心脏肥大发展中的可能作用。为了解决这些问题，Wistar 大鼠用甲状腺素（T（4），0.1mg/kgBW/天，ip）处理，并用或不用 AT（2）R 阻滞剂（PD123319）处理 14 天。心脏肥大通过心脏/体重比来确定，并通过心房利钠因子 mRNA 表达的分析来证实。心肌细胞培养用于排除 TH 相关血流动力学效应的影响。我们的结果表明，TH 诱导的心脏肥大中，心脏 Ang II 水平显著升高（80%，P<0.001），AT（2）R 表达增加（50%，P<0.05）。在给予 AT（2）阻滞剂后，体内 AT（2）R 对这种心脏肥大发展的关键作用得到了证实，该阻滞剂能够预防 TH 诱导的心脏质量增加和 Akt 激活的 40%（P<0.01）。在体外研究中使用 PD123319 后，也证实了 AT（2）R 对 TH 诱导的心肌细胞肥大的作用。这些发现提高了对甲状腺功能亢进症中观察到的心脏肥大的理解，并为未来治疗策略的制定提供了新的见解。
