Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue.
Chymase-dependent generation of angiotensin II from angiotensin-(1-12) in human atrial tissue.
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DOI：
10.1371/journal.pone.0028501
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ferrario CM
中科院分区：
文献类型：
--
作者：
Ahmad S;Simmons T;Varagic J;Moniwa N;Chappell MC;Ferrario CM
由于血管紧张素-（1-12）[Ang-（1-12）]是大鼠组织中产生心脏Ang肽的非肾素依赖性替代前体，我们研究了从9名接受心脏手术以主要控制房颤（迷宫手术程序）的患者的人心耳组织分离的质膜（PM）对Ang-（1-12）的代谢。PM与高度纯化的125 I-Ang-（1-12）在37°C下孵育1小时，有或没有肾素-血管紧张素系统（RAS）抑制剂[赖诺普利用于血管紧张素转换酶（ACE），SCH 39370用于脑啡肽酶（NEP），MLN-4760用于ACE 2，以及糜蛋白酶抑制剂用于糜蛋白酶;各50 μM]。125 I-Ang肽级分通过与在线γ-检测器偶联的HPLC鉴定。在不存在所有RAS抑制剂的情况下，125 I-Ang-（1-12）转化为Ang I（2±2%）、Ang II（69±21%）、Ang-（1-7）（5±2%）和Ang-（1-4）（2±1%）。在不存在所有RAS抑制剂的情况下，仅22±10%的125 I-Ang-（1-12）未被代谢，而在存在所有RAS抑制剂的情况下，98±7%的125 I-Ang-（1-12）保持完整。ACE和糜酶选择性抑制的相对贡献表明，125 I-Ang-（1-12）主要被糜酶转化为Ang Ⅱ（65±18%），而ACE对Ang Ⅱ的水解作用则明显降低或检测不到。基于Ang II形成的量计算单个酶的活性。这些结果表明，125 I-Ang-（1-12）通过凝乳酶介导的Ang II形成非常高（28±3.1 fmol×min−1×mg−1，n = 9），而ACE通过ACE形成非常低或不可检测的Ang II（1.1±0.2 fmol×min−1×mg−1）。 与这些发现相一致，这些组织显示出大量糜酶蛋白，免疫细胞化学显示其主要位于心房心肌细胞中。总之，我们首次在人类心脏组织中证明了心脏糜酶在Ang-（1-12）形成Ang II中的主导作用。
Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified 125I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 µM each]. 125I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, 125I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of 125I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of 125I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that 125I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol×min−1×mg−1, n = 9) from 125I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min−1×mg−1). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12).
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