Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart
Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart
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DOI：
10.1113/expphysiol.2007.040246
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Chappell, Mark C.
中科院分区：
文献类型：
--
作者：
Garabelli, Paul J.;Modrall, J. Gregory;Chappell, Mark C.
血管紧张素转换酶2（ACE 2）是血管紧张素转换酶（ACE）的同源物，其将血管紧张素（Ang）I转化为Ang（1-9），将Ang II转化为Ang（1-7），但不直接将Ang I加工为Ang II。ACE 2基因敲除小鼠的心脏功能受损;然而，ACE 2在鼠心脏内血管紧张素肽加工中的重要性尚不清楚。我们测定了野生型（WT）、ACE（ACE（-/-））和ACE 2敲除小鼠（ACE 2（-/-））中血管紧张素的代谢。血管紧张素II在WT和ACE（-/-）品系的心脏膜中几乎完全转化为Ang（1-7），尽管ACE（-/-）小鼠中Ang（1-7）的产生更多（WT为27.4 +/- 4.1 vs 17.5 +/- 3.2 nmol（-1）mg h（-1））。ACE 2抑制剂MLN 4760显著减弱了两种菌株中的Ang II代谢和随后的Ang（1-7）形成。在ACE 2（-/-）心脏中，Ang II代谢和Ang（1-7）的产生显著减弱;然而，ACE 2抑制剂降低了该菌株中残余的Ang（1-7）形成活性。血管紧张素I主要转化为Ang（1-9）（WT，28.9 +/- 3.1 nmol（-1）mg h（-1）; ACE（-/-），49.8 +/- 5.3 nmol（-1）mg h（-1）;和ACE 2（-/-），35.9 +/- 5.4 nmol（-1）mg h（-1））和较少量的Ang（1-7）和Ang II。虽然ACE 2抑制剂对Ang（1-9）的形成没有影响，但羧肽酶A抑制剂琥珀酸苄酯基本上消除了Ang（1-9）的形成，并增加了心肌膜中Ang I的水平。总之，我们在小鼠心脏中的研究表明，ACE 2是Ang II代谢和随后形成Ang（1-7）的主要途径，与Ang II相比，Ang（1-7）是一种表现出抗纤维化和抗增殖作用的肽。
Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme (ACE), converts angiotensin (Ang) I to Ang(1-9) and Ang II to Ang(1-7), but does not directly process Ang I to Ang II. Cardiac function is compromised in ACE2 null mice; however, the importance of ACE2 in the processing of angiotensin peptides within the murine heart is not known. We determined the metabolism of angiotensins in wild-type (WT), ACE (ACE(-/-)) and ACE2 null mice (ACE2(-/-)). Angiotensin II was converted almost exclusively to Ang(1-7) in the cardiac membranes of WT and ACE(-/-) strains, although generation of Ang(1-7) was greater in the ACE(-/-) mice (27.4 +/- 4.1 versus 17.5 +/- 3.2 nmol(-1) mg h(-1) for WT). The ACE2 inhibitor MLN4760 significantly attenuated Ang II metabolism and the subsequent formation of Ang(1-7) in both strains. In the ACE2(-/-) hearts, Ang II metabolism and the generation of Ang(1-7) were significantly attenuated; however, the ACE2 inhibitor reduced the residual Ang(1-7)-forming activity in this strain. Angiotensin I was primarily converted to Ang(1-9) (WT, 28.9 +/- 3.1 nmol(-1) mg h(-1); ACE(-/-), 49.8 +/- 5.3 nmol(-1) mg h(-1); and ACE2(-/-), 35.9 +/- 5.4 nmol(-1) mg h(-1)) and to smaller quantities of Ang(1-7) and Ang II. Although the ACE2 inhibitor had no effect on Ang(1-9) formation, the carboxypeptidase A inhibitor benzylsuccinate essentially abolished the formation of Ang(1-9) and increased the levels of Ang I in cardiac membranes. In conclusion, our studies in the murine heart suggest that ACE2 is the primary pathway for the metabolism of Ang II and the subsequent formation of Ang(1-7), a peptide that, in contrast to Ang II, exhibits both antifibrotic and antiproliferative actions.