Angiotensin(1-7) Blunts Hypertensive Cardiac Remodeling by a Direct Effect on the Heart
Angiotensin(1-7) Blunts Hypertensive Cardiac Remodeling by a Direct Effect on the Heart
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DOI：
10.1161/circresaha.108.184911
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发表时间：
2008-11-21
影响因子：
20.1
通讯作者：
Reudelhuber, Timothy L.
中科院分区：
文献类型：
--
作者：
Mercure, Chantal;Yogi, Alvaro;Reudelhuber, Timothy L.
血管紧张素转换酶2 （ACE2）将血管加压素血管紧张素II （Ang II）转化为血管紧张素（Ang (1-7)） [Ang(1-7)]，一种具有血管扩张和心脏保护特性的肽。据一组研究报告，小鼠中ACE2基因失活导致Ang II在心脏中积累，并导致与年龄相关的心脏收缩性缺陷。第二项研究证实了ACE2作为Ang II清除酶的作用，但未能重现先前在ACE2缺陷小鼠中报道的收缩性缺陷。这些差异的原因尚不清楚，但可能包括在所使用的小鼠模型中Ang II积累的差异或Ang的缺乏（1-7）。因此，ACE2、Ang II和Ang（1-7）在心脏中的作用仍然存在争议。使用一种新的策略，我们针对转基因小鼠心脏中Ang II或Ang（1-7）的慢性过量产生，并测试了它们对高血压挑战时与年龄相关的收缩性和心脏重塑的影响。我们证明，即使在年龄较大（8个月）的小鼠中，心脏中Ang II的慢性积累也不会导致心脏收缩性缺陷。同样，与年龄匹配的对照组相比，心脏中Ang（1-7）肽增加8倍的转基因动物在静息血压或心脏收缩力方面没有差异，但在高血压应激反应中，它们的心室肥厚和纤维化明显少于非转基因幼鼠。对下游信号级联的分析表明，心脏Ang（1-7）选择性地调节心脏重构的一些下游信号效应物。这些结果表明，Ang（1-7）可以通过对心脏的直接作用来减少高血压引起的心脏重塑，并提出了一种可能性，即与ACE2失活相关的病理部分是由Ang的产生减少介导的（1-7）。（Circ Res. 2008; 103: 1319-1326.）
Angiotensin-converting enzyme 2 (ACE2) converts the vasopressor angiotensin II (Ang II) into angiotensin (1-7) [Ang(1-7)], a peptide reported to have vasodilatory and cardioprotective properties. Inactivation of the ACE2 gene in mice has been reported by one group to result in an accumulation of Ang II in the heart and an age-related defect in cardiac contractility. A second study confirmed the role of ACE2 as an Ang II clearance enzyme but failed to reproduce the contractility defects previously reported in ACE2-deficient mice. The reasons for these differences are unclear but could include differences in the accumulation of Ang II or the deficiencies in Ang(1-7) in the mouse models used. As a result, the roles of ACE2, Ang II, and Ang(1-7) in the heart remain controversial. Using a novel strategy, we targeted the chronic overproduction of either Ang II or Ang(1-7) in the heart of transgenic mice and tested their effect on age-related contractility and on cardiac remodeling in response to a hypertensive challenge. We demonstrate that a chronic accumulation of Ang II in the heart does not result in cardiac contractility defects, even in older (8-month-old) mice. Likewise, transgenic animals with an 8-fold increase in Ang(1-7) peptide in the heart exhibited no differences in resting blood pressure or cardiac contractility as compared to age- matched controls, but they had significantly less ventricular hypertrophy and fibrosis than their nontransgenic littermates in response to a hypertensive challenge. Analysis of downstream signaling cascades demonstrates that cardiac Ang(1-7) selectively modulates some of the downstream signaling effectors of cardiac remodeling. These results suggest that Ang(1-7) can reduce hypertension-induced cardiac remodeling through a direct effect on the heart and raise the possibility that pathologies associated with ACE2 inactivation are mediated in part by a decrease in production of Ang(1-7). (Circ Res. 2008; 103: 1319-1326.)