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

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.

• Authors: Hui Ma, Yu-Lin Wang, Nai-Hao Hei, Jun-Long Li, Xin-Ran Cao, Bo Dong, Wen-Jiang Yan
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 98 Issue 4 Pg. 541-551 (04 2020) ISSN: 1432-1440 [Electronic] Germany
• PMID: 32060588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AVE 0991
• Apolipoproteins E
• Imidazoles
• Lipids
• Peptide Fragments
• Angiotensin II
• Angiotensin I
• p38 Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• angiotensin I (1-7)

Topics

• Angiotensin I (chemistry, pharmacology)
• Angiotensin II (adverse effects)
• Animals
• Aortic Aneurysm, Abdominal (drug therapy, etiology, pathology, prevention & control)
• Apolipoproteins E (deficiency)
• Blood Pressure
• Disease Models, Animal
• Humans
• Imidazoles (chemistry, pharmacology)
• Immunohistochemistry
• Lipids (blood)
• MAP Kinase Signaling System (drug effects)
• Male
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Knockout
• Molecular Mimicry
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Peptide Fragments (chemistry, pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)