Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes
Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes
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DOI：
10.1152/ajpcell.00409.2004
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发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Tallant, EA
中科院分区：
文献类型：
--
作者：
Gallagher, PE;Chappell, MC;Tallant, EA
血管紧张素转换酶2 （angiotensin- converting enzyme, ACE2）是ACE的同源物，它优先从血管紧张素II （angiotensin II, ANG II）生成血管紧张素-(1-7)[ANG-(1-7)]。用ANG II孵育新生大鼠小脑或髓质星形胶质细胞可使ACE2 mRNA减少约60%，提示该酶具有转录调控作用。相比之下，ANG II对两个脑区分离的星形胶质细胞中的ACE mRNA没有影响，表明ANG II对这两种酶的调节存在差异。ANG ii介导的ACE2 mRNA的减少被血管紧张素1型（AT(1)）受体拮抗剂氯沙坦或缬沙坦阻断；血管紧张素2型（AT(2)）拮抗剂PD123319无效。ANG II对ACE2 mRNA的减少也与氯沙坦阻断的小脑和髓质ACE2蛋白减少50%相关。用ANG II的ACE2水解产物ANG（1-7）处理髓系星形胶质细胞，对ACE2 mRNA无影响；然而，ANG-(1-7)阻止了ANG ii介导的ACE2 mRNA的减少。选择性AT（(1-7)）受体拮抗剂[D-Ala(7)]-ANG-(1-7)的加入阻断了ANG-(1-7)的抑制作用。这些数据首次证实了ANG II和ANG-对ACE2的转录调控（1-7）。由于ACE2优先将ANG II转化为ANG-(1-7)， ANG II对该酶的下调在大脑中构成了一个新的正前馈系统，可能有利于ANG II介导的神经反应。此外，ANG-(1-7)在ANG II对ACE2的转录调节中的调节作用表明，这些肽之间存在复杂的相互作用，这种相互作用是由不同的受体系统介导的。
Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that preferentially forms angiotensin-(1-7) [ANG-(1-7)] from angiotensin II (ANG II). Incubation of neonatal rat cerebellar or medullary astrocytes with ANG II reduced ACE2 mRNA by similar to 60%, suggesting transcriptional regulation of the enzyme. In contrast, ANG II had no effect on ACE mRNA in astrocytes isolated from either brain region, demonstrating a differential regulation of the two enzymes by ANG II. The ANG II-mediated reduction in ACE2 mRNA was blocked by the angiotensin type 1 (AT(1)) receptor antagonists losartan or valsartan; the angiotensin type 2 (AT(2)) antagonist PD123319 was ineffective. The reduction in ACE2 mRNA by ANG II also was associated with a 50% decrease in cerebellar and medullary ACE2 protein, which was blocked by losartan. Treatment of medullary astrocytes with ANG(1-7), the product of ACE2 hydrolysis of ANG II, did not affect ACE2 mRNA; however, ANG-(1-7) prevented the ANG II-mediated reduction in ACE2 mRNA. The addition of [D-Ala(7)]-ANG-(1-7), a selective AT((1-7)) receptor antagonist, blocked the inhibitory actions of ANG-(1-7). These data are the first to demonstrate transcriptional regulation of ACE2 by ANG II and ANG-(1-7). Because ACE2 preferentially converts ANG II to ANG-(1-7), downregulation of the enzyme by ANG II constitutes a novel positive feed-forward system within the brain that may favor ANG II-mediated neural responses. Furthermore, the modulatory role of ANG-(1-7) in the transcriptional regulation of ACE2 by ANG II suggests a complex interplay between these peptides that is mediated by distinct receptor systems.