Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart
Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart
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DOI：
10.1210/en.2008-1353
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Li, Yuhao;Saito, Yoshihiko;Nakao, Kazuwa
血管紧张素II在心脏肥大的发生中发挥关键作用。血管紧张素II 1型受体（AT 1）在血管紧张素II诱导的心肌肥大中的作用已得到公认，但AT 2信号转导的作用仍存在争议。以前，我们已经表明，利钠肽受体/鸟苷酸环化酶-A（GCA）信号至少部分地通过抑制AT 1介导的促肥大信号来保护心脏免于肥大。在这里，我们研究了AT 2在缺乏GCA的小鼠中观察到的心脏肥大中的作用。实时定量RT-PCR和免疫印迹方法表明心脏AT 2基因在GCA缺陷小鼠中过表达。单独缺乏AT 2的小鼠没有表现出异常的心脏表型。相反，当AT 2不存在时，GCA缺乏诱导的心脏/体重比、心肌细胞横截面积和胶原积累的增加（如货车Gieson染色所证明的）减弱。此外，在GCA无效动物中，心肌肥厚相关基因的上调表达也被抑制。用PD 123319药理学阻断AT 2同样可减轻GCA缺陷小鼠的心脏肥大。此外，尽管AT 1拮抗剂奥美沙坦可减轻GCA缺陷小鼠的心脏肥大，但该治疗对GCA/AT 2双无效小鼠的心脏肥大没有影响，尽管其在这些动物中具有强效抗高血压作用。这些结果表明，AT 2和AT 1的相互作用可能是重要的心脏肥大的发展。总的来说，我们的研究结果支持GCA抑制心脏中AT 2介导的促肥大信号传导的论断，并为疾病发病机制中的内源性心脏保护机制提供了新的见解。（内分泌学150：3759-3765，2009）
Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis. (Endocrinology 150: 3759-3765, 2009)