Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension.
Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension.
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DOI：
10.1161/hypertensionaha.109.138420
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Batlle D
中科院分区：
文献类型：
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作者：
Wysocki J;Ye M;Rodriguez E;González-Pacheco FR;Barrios C;Evora K;Schuster M;Loibner H;Brosnihan KB;Ferrario CM;Penninger JM;Batlle D
血管紧张素转换酶2(ACE2)裂解血管紧张素II(Ang II)形成Ang-(1-7)。本研究探讨了重组人可溶性血管紧张素转换酶2(RACE2)能否有效降低血管紧张素转换酶II(Ang II)，升高Ang-(1-7)，以及rACE2能否通过全身和局部ACE2活性增强机制预防血管紧张素转换酶II(Ang II)输注引起的高血压。将rACE2通过渗透压小泵注入清醒小鼠或麻醉小鼠，持续三天。RACE2使血清ACE2活性呈剂量依赖性升高，但对肾脏或心脏ACE2活性无影响。在急性实验中，rACE2(1 mg/kg)可拮抗Ang II(0.2 mg/kg)的快速降压作用，这与其降低血浆Ang-(1-7)和降低Ang-(1-7)有关。在血管紧张素Ⅱ输注过程中，血管紧张素Ⅱ受体阻断剂A779(0.2 mg/kg)不影响rACE2的降压作用，而超生理水平的血管紧张素Ⅱ受体阻断剂A779(0.2 mg/kg)对血压无影响。我们得出结论，在血管紧张素Ⅱ输注过程中，rACE2有效地降解血管紧张素Ⅱ，并在此过程中使血压恢复正常。RACE2的作用机制是由于全身而不是组织中ACE2活性的增加和血浆Ang II的降低，而不是Ang-(1-7)的升高。增加ACE2的活性可能通过促进其降解，在Ang II过度活跃的状态下提供一个新的治疗靶点，这一方法不同于目前关注的阻止Ang II的形成和作用。
Angiotensin converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) to form Ang-(1-7). Here we examined whether soluble human recombinant ACE2 (rACE2) can efficiently lower Ang II and increase Ang-(1-7), and whether rACE2 can prevent hypertension caused by Ang II infusion as a result of systemic versus local mechanisms of ACE2 activity amplification. rACE2 was infused via osmotic minipumps for three days in conscious mice or acutely in anesthetized mice. rACE2 caused a dose-dependent increase in serum ACE2 activity but had no effect on kidney or cardiac ACE2 activity. Following Ang II infusion (40pmol/min), rACE2 (1mg/kg/d) resulted in normalization of systolic blood pressure and plasma Ang II. In acute studies, rACE2 (1mg/kg) prevented the rapid hypertensive effect of Ang II (0.2mg/kg), and this was associated with both a decrease in Ang II and an increase in Ang-(1-7) in plasma. Moreover, during infusion of Ang II, the effect of rACE2 on blood pressure was unaffected by a specific Ang-(1-7) receptor blocker, A779 (0.2 mg/kg), and infusing supra-physiologic levels of Ang-(1-7) (0.2 mg/kg) had no effect on blood pressure. We conclude that during Ang II infusion rACE2 effectively degrades Ang II and in the process normalizes blood pressure. The mechanism of rACE2 action results from an increase in systemic, not tissue, ACE2 activity and the lowering of plasma Ang II rather than the attendant increase in Ang-(1-7). Increasing ACE2 activity may provide a new therapeutic target in states of Ang II over-activity by enhancing its degradation, an approach that differs from the current focus on blocking Ang II formation and action.