Patel Vaibhav B, Takawale Abhijit, Ramprasath Tharmarajan, Das Subhash K, Basu Ratnadeep, Grant Maria B, Hall David A, Kassiri Zamaneh, Oudit Gavin Y
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
J Mol Med (Berl). 2015 Sep;93(9):1003-13. doi: 10.1007/s00109-015-1285-z. Epub 2015 Apr 15.
Activation of the angiotensin 1-7/Mas receptor (MasR) axis counteracts angiotensin II (Ang II)-mediated cardiovascular disease. Recombinant human angiotensin-converting enzyme 2 (rhACE2) generates Ang 1-7 from Ang II. We hypothesized that the therapeutic effects of rhACE2 are dependent on Ang 1-7 action. Wild type male C57BL/6 mice (10-12 weeks old) were infused with Ang II (1.5 mg/kg/d) and treated with rhACE2 (2 mg/kg/d). The Ang 1-7 antagonist, A779 (200 ng/kg/min), was administered to a parallel group of mice. rhACE2 prevented Ang II-induced hypertrophy and diastolic dysfunction while A779 prevented these beneficial effects and precipitated systolic dysfunction. rhACE2 effectively antagonized Ang II-mediated myocardial fibrosis which was dependent on the action of Ang 1-7. Myocardial oxidative stress and matrix metalloproteinase 2 activity was further increased by Ang 1-7 inhibition even in the presence of rhACE2. Activation of Akt and endothelial nitric oxide synthase (eNOS) by rhACE2 were suppressed by the antagonism of Ang 1-7 while the activation of pathological signaling pathways was maintained. Blocking Ang 1-7 action prevents the therapeutic effects of rhACE2 in the setting of elevated Ang II culminating in systolic dysfunction. These results highlight a key cardioprotective role of Ang 1-7, and increased Ang 1-7 action represents a potential therapeutic strategy for cardiovascular diseases.
Activation of the renin-angiotensin system (RAS) plays a key pathogenic role in cardiovascular disease. ACE2, a monocarboxypeptidase, negatively regulates pathological effects of Ang II. Antagonizing Ang 1-7 prevents the therapeutic effects of recombinant human ACE2. Our results highlight a key protective role of Ang 1-7 in cardiovascular disease.
血管紧张素1-7/ Mas受体（MasR）轴的激活可对抗血管紧张素II（Ang II）介导的心血管疾病。重组人血管紧张素转换酶2（rhACE2）可从Ang II生成Ang 1-7。我们假设rhACE2的治疗作用依赖于Ang 1-7的作用。将野生型雄性C57BL/6小鼠（10-12周龄）输注Ang II（1.5 mg/kg/d）并用rhACE2（2 mg/kg/d）治疗。将Ang 1-7拮抗剂A779（200 ng/kg/min）给予另一组平行的小鼠。rhACE2可预防Ang II诱导的心肌肥大和舒张功能障碍，而A779则可阻止这些有益作用并引发收缩功能障碍。rhACE2可有效拮抗Ang II介导的心肌纤维化，这依赖于Ang 1-7的作用。即使在存在rhACE2的情况下，Ang 1-7抑制也会进一步增加心肌氧化应激和基质金属蛋白酶2的活性。Ang 1-7的拮抗作用可抑制rhACE2对Akt和内皮型一氧化氮合酶（eNOS）的激活，同时维持病理信号通路的激活。阻断Ang 1-7的作用可阻止rhACE2在Ang II升高导致收缩功能障碍的情况下的治疗作用。这些结果突出了Ang 1-7的关键心脏保护作用，增加Ang 1-7的作用代表了心血管疾病的一种潜在治疗策略。
肾素-血管紧张素系统（RAS）的激活在心血管疾病中起关键致病作用。ACE2作为一种单羧肽酶，对Ang II的病理作用起负调节作用。拮抗Ang 1-7可阻止重组人ACE2的治疗作用。我们的结果突出了Ang 1-7在心血管疾病中的关键保护作用。
