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AVE0991, a nonpeptide angiotensin-(1–7) mimic, inhibits angiotensin II–induced abdominal aortic aneurysm formation in apolipoprotein E knockout mice

  • Hui Ma
  • Yu-Lin Wang
  • Nai-Hao Hei
  • Jun-Long Li
  • Xin-Ran Cao
  • Bo DongEmail author
  • Wen-jiang YanEmail author
Original Article

Abstract

AVE0991, a nonpeptide angiotensin-(1–7) mimic, has similar protective effects for cardiovascular system to Ang-(1–7). In this article, we aimed to explore the effects of AVE0991 and Ang-(1–7) on abdominal aortic aneurysm (AAA) induced by Ang II in apolipoprotein E knockout mice. The mice AAA model was established by Ang II infusion, and then mice received different treatment with saline, Ang II (1.44 mg/kg/day), different dose AVE0991 (0.58 or 1.16 μmol/kg/day), or Ang-(1–7) (400 ng/kg/min). The incidence of AAA was 76%, 48%, 28%, and 24% in the vehicle, the low-dose AVE0991, high-dose AVE0991, and the Ang-(1–7) group, respectively. In comparison with control group, AVE0991 and Ang-(1–7) treatment significantly increased smooth muscle cells and decreased macrophage accumulation, the expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNF-α), and the expression and activity of metalloproteinases 2 and 9 in mice AAA model or in human smooth muscle cells (hVSMCs). The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation, whereas the positive impacts were reversed by co-administration with the Mas antagonist A779 (400 ng/kg/min) and AVE0991 in Ang II–infused mice or in hVSMCs. Therefore, AVE0991 and Ang-(1–7) might be novel and promising interventions in the prevention and treatment of AAA.

Key messages

• AVE0991 dose-dependently inhibited Ang II–induced AAA formation in Apoe−/− mice.

• Ang-(1–7) played the same protective role as high-dose AVE0991.

• Inhibition of Mas receptor with A779 could reverse the protective effect of AVE0991.

• The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation.

Keywords

AVE0991 Angiotensin-(1–7) Abdominal aortic aneurysm Mas receptor Matrix metalloproteinase Inflammation 

Notes

Funding information

This work was supported by the National 973 Basic Research Program of China (No. 2013CB530700), National Natural Science Foundation of China (No. 81570729, 81170207, 81500339), Program of State Chinese Medicine Administration Bureau (No. JDZX2012113), and the Key Research & Development Plan of Shandong Province (NO. 2019GSF108013).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

109_2020_1880_MOESM1_ESM.docx (4.6 mb)
ESM 1 (DOCX 4.61 mb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Pediatrics and Department of CardiologyShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of CardiologyQilu Hospital of Shandong UniversityJinanChina

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